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ORIGINAL PAPER
Medicinal mushrooms in supportive cancer therapies:
an approach to anti-cancer effects and putative
mechanisms of action
Dilani D. De Silva & Sylvie Rapior & Françoise Fons &
Ali H. Bahkali & Kevin D. Hyde
Received: 19 December 2011 / Accepted: 5 January 2012 /Published online: 27 January 2012
#
Abstract Medicinal mushrooms have been valued as natu-
ral sources of bioactive compounds since times immemorial
and have been recognized as potential immunom odulating
and anti-cancer agents. Their consumption has consistently
been shown to have beneficial effects on human health .
Cancer is a generic term for several types of diseases that
can be chronic and are responsible for a large number of
deaths worldwide. Although there has been considerable
progress in modern cancer therapy research, difficulties in
understanding the molecular behavior of various types of
cancers a nd the numerous side effects experien ced by
patients from treatments means that this whole subject area
is still problematic. Thus, biological immunotherapy using
natural bioactive compounds as supportive treatments in
conventional cancer therapies has become in vogue. Bioac-
tive metabolites isolated from medicinal mushrooms have
shown potential successes in cancer treatment as biological
immunotherapeutic agents that stimulate the immune system
against cancer cells. They also act as an effective source of
anti-cancer agents, capable of interfering with cellular signal
transduction pathways linked to cancer d evelopment and
progression. In this revie w we compile available data on
the characteristics of medicinal mushrooms that appear to be
particularly effective as biological immunotherapeutic
agents. Major consideration is given to biological constituents
and the putative mechanisms of action by which bioactive
compounds act on the human body. Consideration is also
given to the benefits that have been claimed for the use of
mushrooms in treating cancer and the future prospects of
using medicinal mushrooms as potent supportive candidate
bioagents for treatment of cancers is discussed.
Keywords Medicinal mushrooms
.
Cancer
.
Anti-cancer
.
Immunomodulation
.
Bioactive metabolites
Introduction
It is thought that the consumption of medicinal mushrooms
can be beneficial to humans through their ability to cure
various diseases (Ying et al. 1987; Hobbs 1995 ; Francia et
al. 1999, 2007;Rapioretal.2000; D idukh et al. 2003;
Ferreira et al. 2010). Medicinal mushrooms have been used
as natural products for centuries in traditional therapies for
D. D. De Silva
:
K. D. Hyde (*)
Institute of Excellence in Fungal Research,
Mae Fah Luang University,
333 M.1 T. Tasud Muang District,
Chiang Rai 57100, Thailand
e-mail: kdhyde3@gmail.com
D. D. De Silva
e-mail: desilvadilani9@gmail.com
D. D. De Silva
:
K. D. Hyde
School of Science, Mae Fah Luang University,
333 M.1 T. Tasud Muang District,
Chiang Rai 57100, Thailand
D. D. De Silva
Department of Botany, Faculty of Science,
University of Peradeniya,
Peradeniya 20500, Sri Lanka
S. Rapior
:
F. Fons
Faculty of Pharmacy, University Montpellier 1, UMR 5175 CEFE,
BP 14491, 15, avenue Charles-Flahault,
34093, Montpellier Cedex 5, France
S. Rapior
e-mail: sylvie.rapior@univ-montp1.fr
A. H. Bahkali
:
K. D. Hyde
Botany and Microbiology Department, College of Science,
King Saud University,
Riyadh 11442, Saudi Arabia
Fungal Diversity (2012) 55:1–35
DOI 10.1007/s13225-012-0151-3
The Mushroom Research Foundation 2012
the treatment of many diseases. There is renewed interest in
using mushrooms in traditional medicines and in establishing
their medicinal properties (Ying et al. 1987; Hobbs 1995;
Chang and Mshigeni 2000;Samorini2001;Lindequistetal.
2010). Species of medicinal mushrooms have a long history of
use in disease treatment in folk medicines, especially in
countries such as China, India, Japan and Korea (Ho bbs
1995, 2000 , 2004, 2005; Chang 1999; Mizuno 1999a, b;
Reshetnikov et al. 2001; Ajith and Janardhanan 2007).
The primary taxa traditionally used in these countries
are Cordyceps spp., Fomes fomentarius, Fomitopsis officina-
lis, Ganoderma lucidum, Grifola frondosa, Inonotus obliquus,
Lentinula edodes and Piptoporus betulinus (Table 1)(Hobbs
1995; Zhu et al. 1998a, b;Mizuno1999a, b; Rapior et al.
2000;Mayell2001;Pöder2005).
The kingdom Fungi is regarded as one of the most
diverse groups of organisms, second only to insects and
generally recogonised as comprising of 1.5 million species
classified in five different phyla; numerous species are
thought to be still undiscovered (Hyde 2001). A recent
estimate even suggested that there may be over 5 million
species (Blackwell 2011). Mushrooms are generally consid-
ered to be the spore-bearing fruiting body of higher fungi (or
macrofungi) and most belong to the Basidiomycota. These
along with some Ascomycota are used in traditional medicine
for treatment of diseases (Chang and Miles 1992; Wasser and
Weis 1999b;MilesandChang1997;Moradalietal.2007;
Ferreira et al. 2010).
Chronicdiseaseshavebecomeagrowingburden
throughout the world (Strong et al. 2005; Beaglehole and
Horton 2010; WHO 2011). Chronic diseases are conditions
that persist for a year or more and result in lifelong disability
(limit the activities associated with daily living), thus caus-
ing a
decreased quality of life (WHO 2008; CDC 2011).
They require ongoing medical attention. Several chronic
diseases such as heart disease, stroke, various cancers,
chronic respiratory diseases and d iabetes, are by far the
leading cause of mortality in the world (CDC 2011; Moullec
et al. 2011; Ninot et al. 2011; WHO 2011). Some mushroom
extracts have been shown to have promising effects on
cardiovascular diseases, cancers, diabetes and many other
diseases as well as having anti-viral, anti-bacterial, anti-
parasitic, anti-inflammatory, nephroprotective, neuroprotec-
tive and hepatoprotective effects (Wasser and Weis 1999a;
Poucheret et al. 2006; Chen and Seviour 2007; Francia et al.
2007; Guillamón et al. 2010; Wasser 2011).
Cancer is a broad term that encompasses a complex
group of more than 100 different types of cancerous diseases
that can develop in the body. Most of these can be consider
as chronic diseases, which represent one of the main health
problems of mankind in the 21st century and have become
the leading cause of death around the world (Stewart et al.
2003; WHO 2004, 2011). The estimates reported by WHO
indicate that 84 million people will die of cancer between
2005 and 2015 if the disease is untreated (CDC 2011; WHO
2011). In the United States, cancer is the second most
common cause of death among children between the years
of 1 and 14 (Jemal et al. 2009). Leukemia (particularly acute
lymphocytic leukemia) is the most common cancer causing
death in these children, followed by cancer of the brain and
other parts of the nervous system (Jemal et al. 2009). As a
chronic disease may cause death or have long lasting
effects throughout the lifetime of an individual, finding
a cure for cancer is a major challenge faced by the whole
world in this century.
Today, conventional cancer therapies mainly consist of
surgery, chemotherapy and radiation therapy, depending on
the type of cancer and the stage of tumor development
inside the body (Gibbs 2000;Chanetal.2009;ACS
2011). The major problem arising from these treatments,
especially radiotherapy and chemotherapy, are that they
invariably result in damage or weakening of the patient’s
natural immunol ogical defenses (which may already have
been damaged by the cancer itself) and numerous side
Table 1 Traditionally used mushroom species
Scientific name Common name Chinese name Japanese name
Cordyceps spp. Caterpillar fungi Summer-grass winter-worm (congcao) Tochukaso
Fomes fomentarius Tinder fungus Mu ti ceng kong jun Tsuriganetake
Fomitopsis officinalis
(Laricifomes officinalis)
Wood conk or Agaricon Ku bai ti Tsugasarunokosikake
Ganoderma lucidum sensu lato Ling zhi Ling zhi or reishi Saruno koshikake
Mannentake
Grifola frondosa Hen of the woods, Dancing mushroom Hui Shu Hua Maitake
Inonotus obliquus Chaga, Cinderconk, Clinker fungus, Bai Hua Rong
Kabanoanatake
Lentinula edodes Shiitake, huagu, snake butter, Xiang gu Shiitake
Piptoporus betulinus Birch polypore Hua bo guan jun Kanbatake
2 Fungal Diversity (2012) 55:1–35
effects, causing serious damage and suffering to the patient
(Devereux et al. 1997; Ratain and Relling 2001;Ehrke
2003; Maduro et al. 2003; Anon 2011).
Curing cancers has now foc used on improving the
patient’s quality of life by modifying the host’s biolo gical
response against the malignant invasion. As a supportive
help to the treatments mentioned above, biological immu-
notherapy (sometimes called immunotherapy, biotherapy, or
biological response modifier therapy) is now gaining more
attention, since it considerably reduces the side effects and
helps to overcome cancer growth (Leung et al. 2006; NCI
2006). This is a relatively new addition to the family of
cancer treatments that includes conventional therapies men-
tioned above. Biological therapies use the body’s immune
system, either directly or indirectly, to fight cancer or to
lessen the side effects that may be caused by some cancer
treatments (Ehrke 2003; Auerbach 2006; NCI 2006; Kakimi
et al. 2009).
There are many forms of biological immunotherapeutic
agents, such as monoclonal anti- bodies, cancer vaccines,
interferons, interleukins, colony-stimulating factors, gene
therapy, and nonspecific immunomodulating agents (NCI
2006). Based on Asiatic ancestral knowled ge, medicinal
mushrooms are receiving more attention due to their
immune-enhancing and stimulatory activities inside the
human body (Kodama et al. 2005; Endo et al. 2010; Ferreira
et al. 2010). Many mushroom-derived extracts are therefore
recognized as immunomodulators or as biological response
modifiers (BRMs) (Mizuno 1999a, b; Wasser a nd Weis
1999a, b; Wasser 2002; Leung et al. 200 6 ; Zhang et al.
2007; Novak and Vetvicka 2009). In particular, medicinal
mushrooms not only act as strong immunostimulators but
also as a source of good anti-cancer agents, capable of
interfering with particular cellular signal transduction path-
ways linked to cancer development and progression (Zaidman
et al. 2005; Petrova et al. 2008; Kudugunti et al. 2010).
Currently, more than 30 species of scientifically identified
medicinal mushrooms have demonstrated anti-tumor activity
in experimental studies (Wasser 2011).
In this review we discuss the biological nature of cancer
and how medicinal mushrooms (also referred to as macro-
mycetes) act as immunomodulatory agents. We identify the
unique characteristics of medicinal mushrooms that qualify
them for immunostimulation and anti-cancer effects and
propose several fields of cancer therapy in which the use
of mushrooms appears to be particularly effective. Major
consideration is given to biological constituents and the
hypothesized mechanisms of action by which bioactive
compounds act on the human body. Finally, we explore
the available nutraceutical and anti-cancer drugs with pos-
sible anti-cancer benefits and discuss the future prospectives
of medicinal mushrooms as a potent supportive cand idate
for treatment of cancers. As a note of caution we must state
that there are many medicinal mushroom products on the
market that claim to have anti-cancer benefits, but in most
cases these claims have not been verified. Therefore, the
purpose of this review is to bring together the available
scientific data relevant to the anti-cancer effects of consum-
ing medicinal mushrooms a nd their products so that the
reader
can
make a balanced judgment as to whether they
might be effective. We do not claim at any stage of this
review that consumption of medicinal mushrooms or their
products can cure cancer.
Basic mechanisms of cancers
In general, cancer is an abnormal growth of cells that tend to
proliferate in an uncontrolled way and, in some cases, to
metastasize or spread (Borchers et al. 2004; Zaidman et al.
2005; Ruddon 2007; NCI 2011). Uncontrolled cell prolifer-
ation can be induced by many factors (biotic and abiotic),
including chemical, physical, or biological agents (Anand et
al. 2008; NCI 2011; WHO 2011).
The early stage of a cancer can be referred to as a
neoplasm, an abnormal mass of tissue which results due to
the autonomous (abnormal proliferation) growth of cells
(Nowell 1986; Franks 1997; Ruddon 2007). The growth of
neoplastic cells exceeds and is not coordinated with the
normal tissues around it. Most neoplasms develope due to
the clonal expansion of a single cell that ha s undergone
neoplastic transformation. The transformation of a normal
cell to a neoplastic cell can be caused by environmental
chemicals, viruses, bacteria, hormones, and chronic inflam-
mations that directly and irreversibly alter the cell genome
(Franks 1997; Anand et al. 2008). This usually results in a
lump or tumor. Neo plasms can be further classified into
benign, potentially malignant (pre-cancer), or malignant
(cancer) (Zaidman et al. 2005).
Cancer is a generic term for malignant neoplasms and
three major developmental stages are often recognized
(Feinberg et al. 2006). The first is initiation, in which a
mutagen binds to the cell DN A and causes damage, which
is insufficient to induce tumor production. The second stage
is activation of a tumor promoter that causes the formation
of small benign tumors (pre-cancer). Finally, in the third
stage, progression, the normal genomic control over the cell
cycle stops, resulting in uncontrolled cell proliferation
(Nowell 1986; Borchers et al. 2004).
Neoplastic cells are characterized by the loss of some
specialized functions and the acquisition of new biological
properties (Fidler 1978; Fr anks 1997; Zaidman et al. 2005).
They are usually less differentiated than normal cells and
contain invading cells, which can multiply in the absence of
growth-promoting factors required for proliferation of nor-
mal cells. Cancer cells are resistant to signals normally
Fungal Diversity (2012) 55:1–35 3
causing programmed cell death (apoptosis). Cancer cells
have limitless replicative potential, sustained angiogenesis
(new blood vessel formation), and tissue invas ion and me-
tastasis (Fidler 1978). Neoplastic cells pass on their heritable
biological characteristics to progeny cells (Abercrombie and
Ambrose 1962; Nowell 1986; Anon 2010).
As noted above, cancer is a generic term for several types
of diseases that may occur in different parts or organs of the
human body (NCI 2011). Although there are many thera-
peutic techniques available in modern medicine to control or
remove cancers, nearly all of them exert some kind of a side
effect that affects the patient in long term (Kumar et al.
2005; ACS 2011).
Biologically active metabolites found in medicinal mush-
rooms may provide anti-cancer action with a minimum of side
effects. Most of them activate natural immune responses of the
host and therefore possibly can be used as supportive treat-
ments for cancer prevention along with conventional therapies
(Gao et al. 2004; Hyodo et al. 2005). Tables 2 and 3 provide
information on some of the commonly used species of mush-
rooms with their reported bioactive metabolites claimed to be
beneficial in cancer treatments.
Major bioactive compounds in medicinal mushrooms
Medicinal mushrooms have shown therapeutic action
against the development of cancer cells, primarily because
they contain a number of biologically active compounds
(Bao et al. 2001a; Petrova et al. 2005;Moradalietal.
2007; Zhang et al. 2007; Lee and Hong 2011). This includes
mainly high molecular weight compounds such as polysac-
charides, proteins and lipids as well as a number of low
molecular weight metabolites such as lectins, lactones, ter-
penoids, alkaloids, sterols and phenolic substances (Kidd
2000;Chanetal.2009; Zhong and Xiao 2009). These
substances have their origins as derivatives from many
intermediates in the pathways involved in primary metabo-
lism. Medicinal mushroom metabolites can therefore broadly
be divided into two groups: (1) high molecular weight metab-
olites and (2) low molecular weight metabolites.
In the natural environment, fungi acquire nutrients from
the surrounding substrata via the vegetative hyphae of the
mycelium (Griffin 1994;Selosse2000). This is used to
acquire the energy required to maintain their primary
metabolism (Isaac 199 7 ). However, under adverse envi-
ronmental conditions where nutrient depletion occurs,
growth of the fungus slows down and parts of the
mycelium switch to using various biochemical pathways
(Isaac 1997). Primary metabolites that have accumulated
in the fungus are converted to different products (known
as secondary metabolites) which are not normally produced
during the active growth and are not essential for normal
vegetative proliferation (Mizuno et al. 1995b; Zjawiony
2004; Erkel and Anke 2008; Zhong and Xiao 2009).
Most of these fungal-derived constituents are important
as bioact ive metabolites that may be active against diseases
such as cancer. Fungal bioactive metabolites provide their
immunomodulating activity mainly through the activation
of the natural immune system of the body of the ho st by
interfering with several signal transduction pathways linked
to cancer development (Zhang et al. 20
07).
It has been
recognized that exceptional/abnormal gene expression is
the fundamental cause of many diseases, including cancer
(Jones and Baylin 2007; Ruddon 2007). Modulation of the
intracellular signal transduction pathways and the activation
of transcription factors regulating gene expression and many
other cell mediated pathways have become novel therapeu-
tic targets for such disorders (Clarke et al. 2001). Important
pathways involved in cancer development are the nuclear
factor-kappa B (NF-κB) pathway, mitogen activated pro-
tein kinase pathway (MAPK), AMP-activated kinase
pathway, protein inhibitory pathways and many mo re
others (Nakamura et al. 2003; Kumar et al. 2004; Zaidman
et al. 2005; Tergaonkar 2006; Petrova et al. 2008;Wongetal.
2010a, b). Significantly, modulation of the nuclear factor-
kappa B (NF-κB) pathway is crucial in cancer development
as it induces the expression of genes coding for antigen
receptors on immune cells, anti-apoptotic factors, cell
adhesion molecules, pro-inflammatory cytokines or chemo
attractants and angiogenesis factors for inflammatory cells
(Kumar et al. 2004).
High molecular weight bioactive metabolites
In this review we refer to the high molecular weight com-
pounds found in medicinal mushrooms that are mainly
polysaccharides, polysaccharide-protein complexes/glyco-
conjugates (glycoprotein s, glycopeptides, proteoglycans)
and proteins which are produced through primary metabo-
lism and essential for their continuous growth and biomass
production (Isaac 1997; Wasser 2002; Moradali et al. 2007;
Erkel and Anke 2008). These metabolites are integral con-
stituents of the fungal fruiting body as well as the mycelium.
Polysaccharides (β-glucans)
Polysaccharides (carbohydrates), belonging to structurally
diverse classes of macromolecules, are polymers that can be
found abundantly in the cell walls of macrofungi. They are
composed of various chemical compositions, including β-
glucans (Mizuno et al. 1992, 1995a, b), hetero-β-glucans,
glycans and heteroglycans (Gao et al. 1996), with immuno-
modulating and anti-tumor properties. Glucans are
4 Fungal Diversity (2012) 55:1–35
Table 2 High molecular weight bioactive compounds of medicinal mushrooms which show anti-cancer effects
Mushroom species Bioactive compounds (and common name) References
Agaricus subrufescens (A. blazei Murrill
A. brasiliensis)
Glucans Oshiman et al. 2002
β-(1→6)-D-polyglucose
Agrocybe cylindracea α-(1→3)-D-glucan Yoshida et al. 1996
Armillaria tabescens α-(1→6)-D-glucan Luo et al. 2008
Auricularia polytricha (1→3)-linked-β-D glucopyranosyl Song and Du 2010
(1→3, 6)-linked-β-D-glucopyranosyl
Calvatia caelata (Lycoperdon utriforme) Peptides Lam et al. 2001
Calcaelin (protein) Ng et al. 2003
Cordyceps sinensis (Ophiocordyceps sinensis) Polysaccharides Sheng et al. 2011
β-(1→3;1→4)-glucan Zhang et al. 2008
Clitocybe nebularis Ricin B-like lectin Pohleven et al. 2009
Cryptoporus volvatus β-(1→3)-glucan Kitamura et al. 1994
Flammulina velutipes FIP-fve immunomodulatory protein Ko et al. 1995
Ganoderma lipsiense (G. applanatum) Exo polysaccharides, glucans Lee et al. 2007a
Usui et al. 1983
Ganoderma lucidum sensu lato Ganopoly Paterson 2006
β-(1→3;1→6)-glucan Gao et al. 2003
Ganoderma polysaccharides
LZ- 8 Lin et al. 2009
Immunomodulatory protein
GSG (G. lucidum spores glucan) Guo et al. 2009
Ganoderma sinensis FIP-gsi immunomodulatory protein Li et al. 2010a
Ganoderma tsugae FIP-gts immunomodulatory protein Hsiao et al. 2008
Grifola frondosa Maitake D-Fraction Matsui et al. 2001
β-(1→3;1→
6)-glucans with xylose and mannose
Hericium
erinaceus Xylan,
glucoxylan, β-glucans Kim et al. 2011
Lee and Hong 2010
Hypsizygus marmoreus Hypsin proteins Lam and Ng 2001
Inonotus obliquus Endo-polysaccharide Kim et al. 2006
α-linked fucoglucomannan Mizuno et al. 1999
Lentinula edodes Lentinan Zhang et al. 2011
β-(1→3;1→6)-glucan
Chain of (1→4), (1→3) glucanose residues with side
chains of (1→4) glucanose
Yu et al. 2010
Lentinus polychrous Polysaccharides Thetsrimuang et al. 2011
Lentinus strigellus Polysaccharides Lin et al. 2004
Leucopaxillus giganteus Galactomannoglucans Mizuno et al. 1995a, b
Phellinus linteus Proteoglycan (Protein-bound polysaccharides) mixed
α/β-linkages and α-(1→6)-branched type
(1→3)-glycans
Kim et al. 2003a
Kim et al. 2003b
Tsuji et al. 2010
Phellinus igniarius Endo-polysaccharide Yang et al. 2009
Chen et al. 2011
Phellinus rimosus Sporocarp extract Ajith and Janaradhanan 2003
Pholiota adiposa (Hypodendrum adiposum) Lectins Zhang et al. 2009
Pleurotus ostreatus β-glucans, Heteroglucans Wasser and Weis 1999a , b
Pleurotus pulmonarius Xyloglucan, proteoglucans Zhuang et al. 1993
Pleurotus citrinopileatus PCP-3A (Nonlectin glycoprotein) immunomodulatory
protein
Chen et al. 2010a
Polyporus umbellatus (Dendropolyporus
umbellatus)
Glucan Yang et al. 2004
Li et al. 2010c
Russula lepida Lectins Zhang et al. 2010
Fungal Diversity (2012) 55:1–35 5
polysaccharides composed of exclusively D-glucose sub
units, while heteroglucans contain side chains of monosac-
charides (i.e., glucose, galactose, mannose, xylose, arabi-
nose, fucose, r ibose or glucuronic a cid) and may have
different combinations of these (Zhang et al. 2007).
Glycans are polysaccharides containing units other than
glucose in their structural backbone (Moradali et al. 2007).
According to the basic sugar component in the main back-
bone, glycans are classified as galactans, fucans, xylans, and
mannans. Heteroglycans contain side chains of different sug-
ars such as arabinose, mannose, fucose, galactose, xylose and
glucose as a main component or in different combinations
(Wasser 2002;Moradalietal.2007).
β-Glucans are one of the major constituents that make up
the cell wall of fungi (Moradali et al. 2007; Novak et al.
2010). The basic β-D-glucans (i.e., linear polymers of D-
glucose with other monosaccharides) are a repeating struc-
ture, with their D-glucose molecules joined together in
linear chains by β-bonds (glycosidic bonds). These can
extend from th e carbo n 1 of one sacchar ide ring to the
carbon 3 of the next β-(1→3), from carbon 1 to carbon 4
β-(1→4), or from carbon 1 to carbon 6 β-(1→ 6). They
differ from each other b y their length and branching struc-
tures (Demleitner et al. 1992;Kidd2000). In different
aqueous solutions, β-glucans undergo conformational
changes into triple helix, single helix or random coils. The
immune functions of β-glucans are apparently dependent on
their conformational complexity (Ohno 2005; Chen and
Seviour 2007; Morad ali et al. 2007; Chen et al. 2008a, b).
Some glucans are linear or branched molecules that have
a backbo ne composed of β-orα-linked glucose units
(Fig. 1a,b), and some of these contain side chains that are
attached at different positions (Wasser 2002; Moradali et al.
2007). The polysaccharide chain is mainly either β-(1→3)
and β-(1→4), or mixed β-(1→3), β
-(1→4) with β-(1→6)
side chains (Kidd 2000). Hetero-β-D-glucans, which are
linear polymers of glucose with other D-monosaccharides,
can have anti-cancer activity, but α-D-glucans from mush-
rooms usually lack anti-cancer activity (Wasser 2002).
It has been suggested that a high degree of structural
complexity is associated with more potent immunomodulatory
and anti-cancer effects (Mizuno et al. 1996;Mizuno1999a, b).
The primary structure and bioactivity of a polysaccharide can
vary according to its monosaccharide composition, configura-
tion and position of glycosidic linkages, sequence of mono-
saccharides, as well as the nature, number and location of
appended n on-carbohydra te groups (Chen and Sevio ur
2007). Mushroom polysaccharides bound to proteins or pep-
tides (polysaccharide-peptides) show higher potent anti-tumor
activity than the corresponding free glucans (Sakagami and
Aoki 1991; Cui and Chisti 2003).
Accordingly, mushroom polysaccharide-protein com-
plexes can have different variations in their chemical struc-
tures such as glycoproteins (Kawagishi et al. 1989)and
heteroglycanprotein complexes (Zhuang et al. 1993;Mizuno
et al. 1996) glycopeptides and proteoglucans (Cui and Chisti
2003; Lee et al. 2010).
Hypothesized mechanism of action of β-glucans
on cancer cells
Mushroom polysacchar ides or β-glucans are thought to
provide their anti-tumor action primarily through the activa-
tion of the immune response of the host organism (immuno-
enhancing activity/immune-modulation activity). In most
cases mushroom polysaccharides do not directly affect tumor
cells. Instead, they help the host to tolerate adverse biological
Table 2 (continued)
Mushroom species Bioactive compounds (and common name) References
Sparassis crispa β-(1→3)-D-glucan Ohno et al. 2003; Ohno et al. 2000
Schizophyllum commune Schizophyllan (sizofiran or SPG) Hobbs 2005
(β-1→3;1→6-glucan) Chan et al. 2009
Taiwanofungus camphorates
(Antrodia camphorata)
Polysaccharides Chen et al. 2010b
Liu et al. 2004
Trametes versicolor Polysaccharide peptide Ooi and Liu 2000
Protein bound β-(1→3;1→6)-glucan
Polysaccharide-Kureha or polysaccharide-K, krestin Price et al. 2010
Immunomodulatory protein Feng et al. 2011
Tremella fuciformis β-(1→3)-D-glucans, heteroglycans with α-(1→3)-mannan
backbone & xylose- and glucuronic acid side chains
Bin 2010
Tremella mesenterica GXM (glucuronoxylomannan α-(1→3)-mannan) Vinogradov et al. 2004
Tricholoma mongolicum Lectins, sugar-binding proteins Wang et al. 1996
6 Fungal Diversity (2012) 55:1–35
Table 3 Low-molecular-weight compounds from mushrooms that exert anti-cancer effects by interfering with cellular signal transduction pathways
Mushroom species Bioactive compounds Anti-cancer effects References
Agaricus subrufescens (A. blazei Murrill,
A. brasiliensis)
Agaritine [β-N-(γ-L(+)-glutamyl)-4-
(hydroxymethyl) phenylhydrazine]
Induction of apoptosis in U937 leukemic cells via
caspase-3/-9 activation through cytochrome c release
from mitochondria.
Endo et al. 2010
Akiyama et al. 2011
Ergosterol Inhibition of neovascularization induced by Lewis lung
carcinoma cells (tumor-induced neovascularization)
Direct inhibition of angiogenesis induced by solid tumors.
Takaku et al. 2001
Agaricus bisporus Caffeic acid phenethyl ester (CAPE) Inhibition of NF-κB binding to DNA Grube et al. 2001
Suppression of aromatase activity
Albatrellus confluens Grifolin Inhibition of tumor cell growth by inducing apoptosis Ye et al. 2005, 2007
Induction of cell-cycle arrest in G1 phase via the
ERK1/2 pathway
Antrodia cinnamomea 4-Acetylantroquinonol B Inhibition of proliferation and growth of hepatocellular
carcinoma cells (HCC).
Lin and Chiang 2011
Arresting of cell cycle via cyclin-dependent kinases
(CDKs) pathway (decreases of CDK2 and CDK4
and increase of the p27)
Armillaria mellea (Lepiota mellea) Arnamial and related sesquiterpene aryl esters Induction of apoptosis in different cancer cell lines Misiek et al. 2009
Kim et al. 2010
Clitocybe alexandri Clitocine [6-amino-5-nitro-4-(β-D-ribo-
furanosylamino) pyrimidine]
Growth inhibitory activity against lung, colon and gastric
human cancer cells.
Vaz et al. 2010
Cordyceps sinensis (Ophiocordyceps sinensis) 5α,8α-Epidioxy-22E-ergosta-6,22-dien-3β-ol Cytotoxic effects on promyelocytic leukemia HL-60 cells Li et al. 2004
Matsuda et al. 2009
Ergosterol Induction of apoptosis through activation of caspases-3/7. Wu et al. 2007
Cordyceps militaris Cordycepin (3′-deoxyadenosine) Induction of apoptosis of human leukemia cells through a
Reactive oxygen species (ROS)-mediated caspase pathway.
Jeong et al. 2011
Cordyceps sinensis Including mitochondrial dysfunction, activation of caspases,
and cleavage of poly (ADP-ribose) polymerase protein.
Trametes versicolor Methanol extract (terpenoids & polyphenols) In-vivo anti-melanoma activity through anti-proliferative,
cytotoxic effects on tumor cells and promotion
of macrophage activity
Harhaji et al. 2008
Ganoderma colossum (Polyporus colossus) Lucidenic acids Inhibition of HepG2 cancer cell invasion by acting as
inhibitor on the phorbol-12-myristate-13-acetate
(PMA)-induced matrix metalloproteinase
(MMP-9) expression.
Kleinwächter et al. 2001
Colossolactones A-G
Ganoderma lucidum sensu lato Lucidenic acid B, triterpenoid compounds,
ganoderic acids, lucidimol, ganodermanondiol,
ganoderiol and ganodermanontriol
Induction of the apoptosis through a signaling cascade
of death receptor-mediated and mitochondria-mediated,
caspase pathways
associated with inactivation
of the Akt signal pathway.
Tang et al. 2006b
Jang et al. 2010
Hsu et al. 2008
Ganoderma lucidum Triterpenoid (ganoderic acid T) Inhibition of tumor metastasis by the suppression of NF-κB
activation likely abrogates the expression of matrix
metalloproteinase MMP-2 and MMP-9.
Xu et al. 2010
Ergosterol Induction of apoptosis Paterson 2006
Fungal Diversity (2012) 55:1–35 7
Table 3 (continued)
Mushroom species Bioactive compounds Anti-cancer effects References
Ganoderma sinensis Ethanol extracts of both G. lucidum and G. sinensis Activities on human breast cancer, hepatoma and
myeloid leukemia.
Liu et al. 2009a
Anti- proliferation effect through apoptosis pathway
and cell cycle arrest effect
Grifola frondosa Triacylglycerols (1-oleoyl-2-linoleoyl-3-
palmitoylglycerol)
Inhibition of Cyclooxygenase activity Zhang et al. 2002
Hericium erinaceus Ethanol extracts containing terpenoids,
sterols and phenols
Apoptosis, suppression of the cell proliferation via activation
of mitochondria-mediated caspase-3 and -9
Kim et al. 2011
Mizuno 1999c
Inonotus obliquus 3β-hydroxy-lanosta-8,24-dien-21-al, inotodiol
and lanosterol
In vivo anti-tumor effects on cancer cells. Chung et al. 2010
Inhibition proliferation of cancer cells through caspase-3
dependent apoptosis (Inotodiol)
Nomura et al. 2008
Lentinula edodes Caffeic acid phenethyl ester (CAPE) Inhibition of NF-κB binding to DNA Mattila et al. 2001
Suppression of aromatase activity
Lentinus crinitus Panepoxydone Interferes with the NF-κB mediated signal by inhibiting
phosphorylation of IkB
Erkel et al. 1996
Lepista inversa Clitocine [6-amino-5-nitro-4-(β-D-ribo-
furanosylamino) pyrimidine]
Anti-tumor effects through the induction of apoptosis Fortin et al. 2006
Bezivin et al. 2003
Leucopaxillus giganteus Clitocine [6-amino-5-nitro-4-(β-D-ribo-
furanosylamino) pyrimidine]
Induction of apoptosis by the activation of caspase-8, 9,
and 3, release of cytochrome c from mitochondria,
decrease of the Bcl-2 level, and increase of the Bax level.
Ren et al. 2008
Marasmius oreades Sesquiterpenes Anti-tumor effects through the blockage of NF-κB activation
at the IκB kinase (IKK) activation pathway.
Petrova et al. 2007, 2009
Mycelia culture extract Inhibition of TNF-α-induced iNOS expression through both
NF-κB and MAPK-dependent mechanisms
Ruimi et al. 2010
Omphalotus illudens Irofulven (6-hydroxymethyl acylfulvene) Inhibition of DNA synthesis, cell cycle arrest in S phase
and induction of caspase-mediated apoptosis.
Alexandre et al. 2007
Derivative of mushroom toxin illudin-S
(sesquiterpene)
Induction of protein oxidation and mitochondrial dysfunction. Herzig et al. 2003
Panus conchatus Panepoxydone Panepoxydone inhibits the TNF-α-
or TPA-induced
phosphorylation
and degradation of IκB.
Umezawa 2006
Cycloepoxydon Cycloepoxydon a potent NF-κB inhibitory activity Zaidman et al. 2005
Phellinus igniarius Phelligridins (pyrano[4,3-c][2]benzopyran-1,
6-dione) derivatives
Cytotoxic activity against several human cancer cell lines Wang et al. 2007
Mo et al. 2004
Phellinus linteus Hispolon Induction of apoptosis by ROS mediated caspase pathway
leading to cytochrome c release & mitochondria dysfunction.
Chen et al. 2008a
Caffeic acid phenethyl ester (CAPE) Inhibition of DNA binding of NF-κB. Nakamura et al. 2003
Induction of the maturation of dendritic cells via NF-κB, ERK
and p38 MAPK signal pathways
Pholiota spumosa Putrescine-1,4-dicinnamide (phenylpropanoid
derivative conjugated with polyamine putrescine)
Induction of apoptosis by ROS mediated caspase pathway
leading to cytochrome c release and necrosis.
Russo et al. 2007
8 Fungal Diversity (2012) 55:1–35
stresses and exert an enhanced immunity against development
of cancer cells by supporting some or all of the major biolog-
ical systems. These are recognized as Biological Response
Modifiers (Parkinson 1995;Mizuno1999b; Wasser and Weis
1999b;Kidd2000; Zhang et al. 2007).
The human immune system has a remarkable ability to
distinguish between the body’s own cells, recognized as
“self” and foreign cells, as “nonself”, to mediate the immune
responses. Mushroom β-glucans are a large group of
macromolecules that are not naturally synthesized inside
the human body, so these compounds are recognized as
non-self molecules which activate the immunity (Brown
and Gordon 2005).
Based on in vivo and in vitro studies on animals, it has
been found that β-glucans rapidly enter the proximal small
intestine (Fig. 2) and are captured by the macrophages after
oral administration (Hong et al. 2004;Riceetal.2005;
Lehne et al. 2006; Chan et al. 2009). The β-glucans are
then divided into smaller sized β-glucan fragments and are
carried to the bone marrow and endothelial reticular system
(Hong et al. 2004). These small fragments are then released
by the macrophages and taken up by the circulating gran-
ulocytes, monocytes and dendritic cells (Hong et al. 2004;
Rice et al. 2005). A natural immune respon se then is initi-
ated with the support of β-glucans (Chan et al. 2009).
The human immune system consists of two major func-
tional units, including the innate immune system and the
adaptive or acquired immune system (McNeela and Mills
2001; Revillard 2002; Uthaisangsook et al. 2002). Innate
immunity is present from the very beginning of an organism’s
life and is relatively non-specific, capable of responding to
many but not all structurally related antigens (Uthaisangsook
et al. 2002). The innate immune system does not confer long-
lasting immunity against a pathogen (Brown and Gordon
2001;Munzetal.2005).
Certain β-glucans from medicinal mushrooms appear to
activate cell-mediated and humoral immunity via activation
of different immune cells, leading to elimination of tumor
cells or pathogens (Ladanyi et al. 1993; Kim et al. 1996;
Kurashige et al. 1997; Brown
et al. 2002). The activated
macrophages (containing β-glucans) preferentially attack
dead cells and intracellular pathogens (Munz et al. 2005).
These macrophages also produce cytokines that prime
natural killer (NK) cells and T lymphocytes, both of
which are cytotoxic to tumor cells, via different mechanisms.
Natural killer cells (NKs) secrete chemical substances that
destroy tumor cells by bursting cell membranes. Neutrophils
effectively destroy targeted cells by cell mediated phagocytosis
(Prestwich et al. 2008).
The adaptive immune system allows for a stronger im-
mune response as well as immunological memory, where
each pathogen is “remembered” by a signature antigen
(Revillard 2002; Munz et al. 2005). The adaptive immune
Table 3 (continued)
Mushroom species Bioactive compounds Anti-cancer effects References
Polyporus umbellatus (Dendropolyporus
umbellatus)
Cytotoxic steroids ergones (22E, 24R)-ergosta-7,
22-dien-3β-ol
Anti-cancer activity against HepG2 cells. Zhao et al. 2010b
Poria cocos (Wolfiporia extensa) Lanostane-type triterpene acids Inhibitory effect on skin tumor promotion. Akihisa et al. 2009
Taiwanofungus camphorates
(Antrodia camphorata)
Terpenoids(zhankuic acid A,C) maleic and
succinic acid derivatives
Induction of apoptosis via suppression of the expression of
apoptosis associated proteins
Chen et al. 2010b
Yeh et al. 2009
Nakamura et al. 2004
Thelephora aurantiotincta Thelephantin O, vialinin A, (p-terphenyl derivatives) Anti-cancer activity against HepG2 and human colonic
carcinoma cells.
Norikura et al. 2011
Fungal Diversity (2012) 55:1–35 9
response is antigen-specific and requires the recognition of
specific “non-self” antigens in a process with combinational
effect of T-cells (T lymphocytes) and B-cells (B lympho-
cytes). T-cells are mainly responsible for inducing cell-
mediated immunity, whereas B cells produce antibodies that
mediate humoral immunity (McNeela and Mills 2001;
Revillard 2002).Theadaptiveimmuneresponsealso
involves dendritic cells, derived from monocytes, and these
present antigens to T-cells for activation of immune
responses (Munz et al. 2005). Cytotoxic T-cells secrete
cytokines that stimulate cell mediate immunity to produce
other tumoricid al chemical substa nces (Trinchieri 2003;
Munz et al. 2005).
The hypothesiz ed mec ha nism of action for fungal β-
glucans against cancer cells in Fig. 3 is composed of a
complex series of reactions inducing innate and adaptive
immune systems (Chan et al. 2009 ). It should be noted,
however, that all of these hypothesized mechanism of
actions are based on animal data and there is very little
evidence from human trials (Kn udsen et al. 1993; Hong et
al. 2004; Rice et al. 2005; Lehne et al. 2006; Vetvicka et al.
2007; Vos et al. 2007).
Membrane receptors involved in immune-modulation
Immune-modulation is a novel cancer treatment that
involves indirect activation of the patient’s natural immune
defense system against pathogens (NCI 2006). Fungal β-
glucans act as immunostimulants, involving both innate and
adaptive immune responses. The reactor cells included in
this process are monocytes, macrophages, dendritic cells,
natural killer cells and neutrophils (M unz et al. 2005;
Chen and Seviour 2007;Chanetal.2009). β-G lucans
also enhance phagocytosis and trigger a cascade of cytokine
release, such as Tumor Necrosis Factor-alpha (TNF-α)and
various types of interleukins (Leung et al. 2006;Chenand
Seviour 2007).
The immune system of a multicellular organism is com-
prised of some special protein receptors called pattern recog-
nition receptors, which detect strange compounds or nonself
structures in the body (Leung et al. 2006; Chen and Seviour
2007). The microbe-specific molecules (nonself) that are rec-
ognized by a given pattern recognition receptors are called
pathogen-associated molecular patterns. Thus, fungal β-
glucans act as pathogen -associated molecular patterns on
OR
OH
O
OH
CH
2
OH
(a)
O
OH
CH
2
O
OH
OH
O
R
O
R
H
O
OH
CH
2
OH
O
(b)
O
C
H
OH
O
OH
H
2
OH
O
O
R
β
α
α
β
Fig. 1 Schematic
representation of the molecular
structure of β-(1→3)-
D-glucans (a), and α-(1→3)-
D-glucans (b)
Fig. 2 β-glucan activation of macrophages (based on Chan et al. 2009 with modifications)
10 Fungal Diversity (2012) 55:1–35
these cell membrane receptors and trigger the immune function
(Brown and Gordon 2005). In humans, a number of different
receptors have been identified. These are dectin-1, comple-
ment receptor-3, scavenger receptors, lactosylceramide, and
toll-like receptors (Gantner et al. 2003;Rogersetal.2005;
Brown 2006).
Evidence suggests that dectin-1 is a type II transmem-
brane protein receptor that binds β-(1→3) and β-(1→6)-
Cytokine
TNF-α, IL-2, IL-10, IL-12
Targeted cell lysis
Adaptive immunit
y
LacCer
Cell mediate
immunity
Humoral immunity
Phagocytosis
of targeted cells
Innate immunity
Fig. 3 Hypothesized
immunostimulatory mechanism
of action of β-glucans on im-
mune cells (Chan et al. 2009)
Fungal Diversity (2012) 55:1–35 11
glucans and is most important in the activation of innate
immune responses i n macrophages (Her re et al. 2004;
Willment et al. 2005). Binding of dectin-1 with β-glucans
activates several signaling pathways to promote innate im-
mune responses through activation of phagocytosis, reactive
oxygen species production, and induction of inflammatory
cytokines (Willment et al. 2001; Grunebach et al. 2002).
Toll-like receptors are a group of transmembrane protein
receptors which respond to microbes, including fungi, bac-
teria, viruses and protozoa. This group of protein receptors
may include about 11 members (Roeder et al. 2004). Toll-
like receptor-2 induces the synthesis of various signaling
pathways, including increasing levels of NF-κB and cyto-
kine production, including TNF-α and interleukin (IL-12),
which is mediated during many immune responses. Most
recent studies have concluded that constituents from poly-
saccharopeptide krestin act as ligands for toll-like receptors-
4, leading to induction of TNF-α and interleukin (IL-6)
inflammatory cytokines (Price et al. 2010). Although their
immune activities are still unclear, complement receptor-3;
scavenger receptors and lactosylceramide receptors are also
important in immune function (Thornton et al. 1996; Xia
and Ross 1999).
Some evidence suggests that in a number of instances these
receptors might act synergistically with each other to produce
strong inflammatory responses by stimulating cytokines such
as TNF-α, interleukins (IL-2 and IL-12) (Ariizumi et al. 2000;
Takeda et al. 2003; Diniz et al. 2004).
Selected examples of important mushroom
polysaccharides with anti-tumor activity
Mushroom-derived β-glucans have been used for centuries
for health purposes. β -glucans have also been the subject of
extensive research and are recognized as potential anti-
cancer agents (Hobbs 1995; Kodama et al. 2002a, b; Zhang
et al. 2005; Boonyanuphap and Hansawasdi 2010). β-
Glucans derived from many different mushrooms, both
cultivated and wild species, such as lentinan, schizophyllan,
maitake D fraction, Ganoderma polysaccharides and Krestin
have been approved in several countries as prescription drugs
for the treatments of cancer (Mizuno 1999b;Girzaletal.2011;
Shang et al. 2011). Among the large pool of anti-tumor poly-
saccharides isolated from medicinal mushrooms (Table 2),
several important examples are described below.
Lentinan
Lentinan is an anti-tumor polysaccharide produced by Lenti-
nula edodes, which is commonly known as the Shiitake mush-
room. This mushroom is widely consumed as a nutritional
health food throughout the world, particularly in Asia, and is
known to have very strong host-mediated anti-cancer activity
via activation of the human immune system (Cheung 2008;
Zhang et al. 2011). The chemical structure of lentinan is a β-
(1→3)-D-glucan having two β-(1→6)-D- glucopyr anoside
branches for every five β-(1→3)-D-glucopyranoside linear
linkages, with a moderate molecular weight of 5–15×10
5
Da
(Zhang et al. 1999, 2001).
The molecular weight and a triple-helical conformation are
known to be important factors for the immune-stimulating
activity of lentinan (Bohn and BeMiller 1995). Triple-helical
lentinan exhibits the strongest anti-cancer activity in mouse
model experiments, with an inhibition ratio of 49.5%, which is
close to that of a reference anti-cancer drug. Such bioactivity
rapidly decreased when the po lysaccharide changed to a
single-flexible chain, thus showing the correlation between
anti-cancer activity and the triple-helix structure of lentinan
(Zhang et al. 2005;Surenjavetal.2006).
The effective anti-cancer properties of lentinan were first
reported by Chihara et al. (1969, 1970), using sarcoma 180
cancer cells transplanted into CD-1/ICD mice. Lentinan was
shown to inhibit the growth of the cancer cells (Chihara et
al. 1970). Lentinan has also satisfactorily been proven to
potentiate human immunity (Wasser and Weis 199 9a;
Hobbs 2000). The immunostimulatory effects of lentinan
involve the activation of numerous immune cells and modu-
lating the release of cell signal messengers such as cytokines
and chemical messengers such as nitric oxide, which increase
the engulfing ability of immune cells (Ooi and Liu 1999;Hou
and C hen 2008). The increase in cytokine production in
immune cells has been demonstrated to be lentinan dose-
dependent and inhibited the expression of caspase-3 in mice
with liver cancer, reducing tumor growth (Shin et al. 2003;
Lull et al. 2005;Fuetal.2011).
The effect of chemically modified lentinan on the immune
response indicates that sulfation can enhance the efficacy of
lentinan to improve the human immune response to vaccines
by enhancing the population of anti-body and white blood
cells (Guo et al. 2008).
Open-label clinical studies indicate that lentinan can pro-
long life in patients with gastric, ovarian or colorectal cancer,
as reviewed by several researchers (Borchers et al. 1999;
Fujimoto et al. 2006).
Schizophyllan
Schizophyllan, sizofiran or SPG is another extensively stud-
ied mushroom-derived polysaccharide with immune modu-
lating activity. This polysaccharide is obtained from the
mushroom Schizophyllum commune and has been used in
cancer treatment practices in several Asian countries (Furue
1987; Wasser 2002). Schizophyllan is a β-(1→3)-D-gl ucan,
12 Fungal Diversity (2012) 55:1–35
having β-(1→6)-D-glucopyranoside side branches at every
three repeating units, and it has received great interest be-
cause of its reversible coiled-helix transition. This generates
a very stiff triple-helical structure in water, with a molecular
weight of ~450,000 Da in neutral aqueous solutions
(Yoneda et al. 1991). Although schizophyllan is similar to
lentinan in composition and anti-tumor activity (Jong et al.
1991), the kinetics of gene expression of cytokines in schiz-
ophyllan have been shown to be different in several studies
(Nemoto et al. 1993; Okazaki et al. 1995). Recently, new
folate-conjugated schizophyllan showed specific a ffinity
toward folate binding proteins a nd as a non-cy totoxic
cancer-targeting antisense carrier that mediated effective
antisense activity in cancer cells (Hasegawa et al. 2005).
Schizophyllan displayed anti-tumor activity against several
carcinomas and sarcoma cell lines (Wasser 2002;Hobbs
2005) and has been studied for its anti-cancer activity and
used for the immuno therapy of stage II or III c ervical
cancers in combination with radiotherapy (Furue 1987;
Sakagami et al. 1988 ; Shimizu et al. 1989). Clinical evalu-
ation of schizophyllan as a surpportive agent on immuno-
therapy i n treatment of head and neck cancer showed
increased recovery rates in cancer patients when compared
to a control group (Kimura et al. 1994).
Maitake D-fraction
This is a mixed β-D-glucan fraction prepared from the fruiting
bodies of the mushroom Grifola frondosa (Maitake). This
well known mushroom has been used as a food in Japan for
hundreds of years, as people have believed in its medicinal
properties (Mizuno 1999b;Mayell2001). Maitake D-fraction
contains mainly β-D-glucan material with β-(1→6) main
chains and β-(1→4) branches, and the more common β-
(1→3) main chains and β-(1→6) branches (Nanba 1997a;
Matsui et al. 2001).
Experimental evidence has shown that maitake D-
Fraction is a good apoptosis inducer and immune enhancer
(Nanba 1997a, b; Konno 2001; Kodama et al. 2002a, b;
Masuda et al. 2010). Most recent findings have confirmed
the apoptotic effect of maitake D-fraction in breast cancer
cells by upregulation of BAK-1 gene activation and further
highlight the
involvement of cytochrome C (Soares et al.
2011). Studies also suggest that the anti-tumor activity is
also possibly related to the carcinoma angiogenesis induction
(Matsui et al. 2001).
In 1998, the Food and Drug Administration (FDA) granted
Maitake products, as an investigational new drug application
(IND), to conduct a phase II pilot study using maitake D-
fraction on patients with advanced breast and prostate cancers
(Nanba 1995;Anon1999;Konno2001). Several in vivo and
in vitro studies tested the chemosensitizing effect of the
maitake fraction to improve the efficacy of chemotherapy
and reduce possible side effects (Kodama et al. 2002b;Louie
et al. 2010). Reduction of the immunosuppressive effect of
chemotherapeutic drugs occurred as a result of an increase in
the proliferation differentiation and activation of immune-
competent cells and thus provided a potential clinical benefit
for patients with cancer (Kodama et al. 2002b, 2005). Inves-
tigations showed the anti-tumor functions of D-Fraction in
relation to its control of the balance between T lymphocyte
subsets Th-1 and Th-2 and potentiated the activation of helper
T-cells, resulting in enhanced cellular immunity and as a
useful immunotherapeutic agent for cancer patients (Kodama
et al. 2002b; Inoue et al. 2002).
Ganoderma polysaccharides
Mushrooms belonging to the genus Ganode rma are some of
the oldest traditional medicines. In particular, Ganoderma
lucidum (Reishi or Ling-Zhi) has been used extensively in
traditional Chinese medicine as a tonic for promoting good
health, perpetual you th, vitality, and longevity (Ying et al.
1987; Hobbs 1995; Chang and Mshigeni 2000).
This species has been intensively studied in recent years
because of its intrinsic immunomodulating and anti-tumor
properties (Liu et al. 2009a; Shang et al. 2011; Ye et al.
2011). It has become more important because the polysac-
charides isolated from its fruiting bodies include some in
which the mai n active ingredients contain (1→3) and/or β-
(1→6)-D-glucans (Hung et al. 2008).
These polysaccharides have been reported to enhance the
cytotoxic activity of natural killer cells and to increase TNF-
α and interferon-γ release from macrophages and lympho-
cytes, respectively (Gao et al. 2004; Kuo et al. 2006).
Recently, a crude extract of the polysaccharide from fruiting
bodies has been reported to induce cytokines expression via
a toll-like receptors-4 modulated protein kinase signaling
pathway (Guo et al. 2009). Heteropolysaccharide–protein
complexes with protein contents of 13.5 and 20.1% have
also been isolated from the mycelium of Ganoderma tsugae
and have been shown to have anti-tumor activities (Peng et al.
2005). It is generally believed that the compounds obtained
from the mycelium are normally quite different from the
metabolites of the same compound class derived from its
sp
or
ocarps. As such, these results should be tested further.
The biological activities reported i n preparations of
Ganoderma mostly emphasize met abolites that include
mainly polysaccharides and terpenoids. Research indicates
that triterpenes from G. lucidum directly suppress growth
and invasive behavior of cancer cells (Sliva 2003). On the
other hand, the polysaccharides stimulate the immune sys-
tem, resulting in the production of cytokines and activation
of anti-cancer activities of immune cells, thus resulting
Fungal Diversity (2012) 55:1–35 13
in a high synergistic effect (Gao et al. 2004;Anon2006;
Paterson 2006).
In recent years, much attention has been paid to the
chemical components of G. lucidum spores and their versa-
tile biological activities. It has been found that one such
compound produces potential immunomodulatory effects
and anti-tumor activities characterist ic of a water-soluble
polysaccharide, with proliferative response of splenocytes
and induced anti-tumor activity against Lewis lung cancer in
mice. It was an effective inducer of the MAPK pathway and
spleen tyrosine kinase Syk-dependent TNF-α and
interleukin-6 secretion in murine resi dent peritoneal
macrophages (Guo et al. 2009). Moreover, the chemically
modified α-D-glucan from spores of G. lucidum shows
increasing stimulati ng effects of lymphocyte proliferatio n
and antibody production when compared to unmodified
glucans (Bao et al. 2001a, b).
In vitro and in vivo experimental evidence has demon -
strated the chemopreventive effects of G. lucidum on cancer
invasion and metastasis and it has been concluded that these
effects occur through the modulation of kinase signaling and
subsequent inhibition of activator protein-1 and NF-κB
(Weng and Yen 2010 ). Most recent research found that the
immunostimulatory activity of a proteoglycan fraction, (LZ-
D-7), isolated from the fruiting body, activates the B-cells
and could be an immunostimulatory drug to improve the
immune response of tumor patients (Ye et al. 2011). Another
study illustrated the induction of apoptosis by ethanol
extracts of G. lucidum in human gastric carcinoma ce lls
(Jang et al. 2010).
Polysaccharide—protein complexes (glycoproteins,
glycopeptides, proteoglucans)
Medicinal mushrooms show an immunostimulatory activity
not only because of bioactive polysaccharides but also in
having varying combinations of polysaccharide-protein
complexes or glycol-conjugates such as glycoproteins,
glycopeptides and proteoglucans (Moradali et al. 2007). Poly-
saccharides can reach a higher level of complexity when they
are covalently bound to other conjugate molecules such as
polypeptides and proteins.
Glycoproteins are proteins that contain oligosaccharide
chains (glucans) covalently attached to polypeptide side-
chains. They are composed of a protein core that is surrounded
by numerous glucan chains bound to protein moiety through
O- or N-glycosidation (Wasser 2002;Moradalietal.2007).
Agaricus subrufescens (0 Agaricus blazei Murrill sensu Hei-
nemann) is a well-known mushroom having several biologi-
cally active metabolites, including polysaccharides and
glycoproteins that are thought to be responsible for its immu-
nostimulant and anti-tumor properties (Firenzuoli et al.
2008). A α-(1→4)-Glucan-β-(1→6)-glucan-protein com-
plex isolat ed fro m A. subruf escens
showed tumor
g
r
owth-inhibitor y effect through the host-mediated mecha-
nisms, and several clinical trials have shown its pharmacolog-
ical benefits on cancer treatment and immunostimulation
(Gonzaga et al. 2009; Ishii et al. 2011).
Glycopeptides from Trametes versicolor
The best known commercial glycopeptide preparatio ns of
Trametes versicolor are polysaccharopeptide and polysac-
charopeptide krestin. Both products are extracted from T.
versicolor and have similar physiological activities but are
structurally different. Polysaccharopeptide and polysacchar-
opeptide krestin are produced from CM-101 and Cov-1
strains of T. vers icolor, respectively. Polysaccharopeptide
and polysaccharopeptide krestin contain α-(1→4) and β-
(1→3) glucosidic linkages in their polysaccharide chain,
with D-glucose as the major monosaccharide present (Ng
1998). Arabinose and rhamnose are the other principal
monosaccharides in the polysaccharopeptide, while po lysac-
charopeptide krestin contains fucose (Cui and Chisti 2003).
Polysac charopeptide krestin seems to work du ring the
multiple steps of cancer metastasis by inhibiting adhesion,
invasion, motility, and metastatic growth of tumor cells in
animal models. Adhesion and invasion are inhibited by
suppression of cell matrix-d egrad ing e nzyme production
by malignant cells (Katano et al. 1987 ; Kobayashi et al.
1995). Motility of malignant cells and subsequent attachment
to blood vessels are inhibited by suppression of tumor-cell
induced platelet aggregation and anti-angiogenic factors (Abe
et al. 1990; Tanaka et al. 1991). Polysaccharopeptide krestin
has also been shown to induce apoptosis (programmed cell
death) in lymphoma, leukemia and pancreatic cells (Hattori et
al. 2004; Jiménez-Medina et al. 2008). Transforming growth
factor β1(TGF-β1) and matrix metalloproteinases (MMPs)
produced by tumor cells are regarded as important factors in
tumor invasion. Evidence clearly shows that polysaccharo-
peptide krestin inhibited in vitro tumor invasiveness through
suppression of MMPs and TGF-β1andwouldseemtohave
possible use as an anti-metastatic drug, with more research
planned in the future (Zhang et al. 2000).
Polysaccharopeptide krestin has been reported as a prom-
ising biological response modifier for clinical use of cancer
patients in Japan (Kidd 2000), which remarkably prolongs
survival and reduces the recurrence of tumors. The potential
use of polysaccharopeptide krestin as an adjuvant for other
conventional cancer therapies has been reported in many
clinical studies (e.g., Torisu et al. 1990; Wan et al. 2008). A
meta-analysis of randomized trials was conducted to evalu-
ate the effectiveness of adjuvant immune-chemotherapy
with polysaccharopeptide krestin for patients with gastric
14 Fungal Diversity (2012) 55:1–35
cancer. I t has been suggested that ad juvant immune-
chemotherapy with polysaccharopeptide krestin improves
the survival of patients after curative gastric cancer resection
(Oba et al. 2007 ). The colon cancer patients who responded
bette r to immunochemotherapy wi th polysaccha ropeptide
krestin support the presence of active diffuse nuclear accu-
mulation type β-catenin (Yamashita et al. 2007). The effect
of polysaccharopeptide krestin as an adjuvant treatment on
non-small cell lung cancer patients after radical radiotherapy
indicates satisfactory tumor shrinkage as compared to the
non-administrated group (Hayakawa et al. 1993).
Proteoglycans from Phellinus linteus
Proteoglycans are proteins that consist of a core protein with
one or more covalently attached glycosaminoglycan chain
(s) that are heavily glycosylated (Moradali et al. 2007). It
has been reported that t he proteogly ca ns (protein-b o und
polysaccharides) from the fruiting bodies or mycelium of
Phellinus linteus stimulate the h ormonal and cell-mediated
immune functions (Kim et al. 2003a, b, 2007) as well as
suppressing tumor growth and metastasis. Lee et al. (2010 )
demonstrated anti-angiogenic activity in a methanolic
extract of P. l in te u s , which revealed a novel inhibitor
of angiogenesis, especially for tumor treatment and preven-
tion. Studies suggest that P. linteus can act as an immune-
potentiator and as a direct inhibitor of cancer cell adhesion
(Han et al. 1999, 2006).
Most recently, the anti-cancer effect of an orally admin-
istered powder of freeze dried mycelia culture of P. linteus
on mice bearing the Hep3B hepatoma cell line was investi-
gated. Immune-modulatory and anti-tumor effects were
established through increased secretion of interleukin-12,
interferon gamma and TNF-α, which enhanced the activity
of natural killer cells. These results also showed that an
improved strain of P. linteus grown on germinated brown
rice inhibited lung met astasis (Huang et al. 2011; Jeon et al.
2011). The important benefit of P. linteus fruiting body
extracts (including proteoglucan s an d po lysaccharides)
compares favorably to conventional chemotherapeutics such
as adriamycin, with its effective suppression of tumor
growth and metastasis through the immune-potentiation of
patients without any toxic effect (Zhu et al. 2008)
Bioactive mushroom proteins
Apart from the most extensively studied polysaccharide
fraction, bioactive proteins constitute the second most abun-
dant functio nal component in mushrooms (Ferreira et al.
2010; Wong et al. 2010a, b). Mushrooms produce a large
number of proteins with significant biological activities,
including lectins, ribosome inactivating proteins (RIPs),
fungal immunomodulatory proteins (FIPs) and laccases
(Wang et al. 1998; Wong et al. 2010a; Xu et al. 2011).
Lectins are proteins that can bind to cell surface carbohy-
drates, with an ability to produce cell agglutination and that
show several anti-proliferative and anti-tumor activities
against cancer cell lines (Zhang et al. 2009,
2010).
Lectin
s
are abundant in many species of mushrooms,
including Agaricus bisporus, Pleurotus ostreatus, Tricholoma
mongolicum, Agaricus subrufescens and Grifola frondosa
(Wang et al. 1998). Recently discovered lectins from the
mushroom Russula lepida and Pholiota adiposa showed
anti-proliferative activity towards hepatoma HepG2 cells and
breast cancer MCF-7 cells (Zhang et al. 2009). The protein
involved belongs to the ricin B-like lectins and has been
designated as Clitocybe nebularis lectin (CNL) and showed
anti-proliferative effects elicited by binding to carbohydrate
receptors on human leukemic T cells (Pohleven et al. 2009).
The ribosome inactivating proteins (RIPs) have a n
enzymatic activity that can suppress the ribosomes by
eliminating parts of adenosine residues from rRNA. A
new ribosome inactivating protein with anti-proliferative
activity from the mushroom Hypsizigus marmoreus potently
inhibited proliferation of HepG2 hepatoma, MCF-7 breast
cancer cells and decreased the HIV-1 reverse transcriptase
activity (Wong et al. 2008).
Fungal immunomodulatory proteins (FIPs) are a new
class of bioactive proteins, wi th targeting ability of immune
cells, isolated from mushrooms (Xu et al. 2011). Six fungal
immunomodulatory proteins (FIPs), LZ-8, gts, gja, fve, vvo
and gsi, have bee n isolated and purified, including three
from Lingzhi mus hrooms, LZ- 8 (Gan oderma lucidum)
(Kino et al. 1989), FIP-gts (Ganoderma tsugae) (Hsiao et
al. 2008) and (F IP-gs i) (Ganoderma sinensis) (Li et al.
2010a), two from edible mushrooms, FIP-fve (Flammulina
velutipes) (Ko et al. 1995) and then FIP-vvo (Volvariella
volvacea) (Maiti et al. 2008).
The fungal immunomodulatory protein, Ling Zhi-8 (LZ-
8), which was isolated and purified from the mycelia of G.
lucidum in 1989, has been regarded as one of the most
important bioactive substances of G. lucidum. The native
form of LZ-8 is a noncovalently bound homodimer with a
molecular mass of 24 kDa. Each polype ptide consists of 110
amino acid residues with acetylated N terminals (Kino et al.
1989). Currently, several studies have been designed to
develop an efficient preparation of new recombinant immu-
nomodulatory proteins with higher activity (Lin et al. 2009,
2010). The immune modulatory effects of rLZ-8 (recom-
bined Ling Zhi-8) on human monocyte-derived dendritic
cells have demonstrated that binding of rLZ-8 to toll like
receptor-4 could effectively induce the significant activation
and maturation of human dendritic cells (Lin et al. 2009).
Dendritic cell s were activated via the NF-κB and MAPK
Fungal Diversity (2012) 55:1–35 15
pathways and it has been proposed that rLZ -8-mediat ed
signal transduction occurs in the regulation of interleukin-
12, 10, p40 and expression (Kino et al. 1989; Lin et al.
2009). A new recombinant immunomodulatory protein,
purified from Ganoderma microsporum, with anti-metastatic
effect also has been found. It can inhibit epidermal growth
factor mediated migration and invasion in A549 lung cancer
cells (Lin et al. 2010).
For the first time (Lin et al. 2011) reported that LZ-8 acts
as a promising adjuvant that enhances the efficacy of a DNA
cancer vaccine by activating dendritic cells and promoting
innate and adaptive immune responses through toll like
receptor 4. This is the first study to apply LZ-8 to a DNA
vaccine model for cancer therapy and determine the immu-
nogenicity in vivo. These data provide a new insight for the
application of LZ-8 for enhancing immunity in vaccine
technology for preventing and treating various cancers.
A comparison between the functions of polysaccharides
and protein LZ-8 from Reishi (G. lucidum) in regulating
murine macrophages and T lymphocytes demonstrated that
LZ-8 could activate murine macrophages and T lympho-
cytes but Ganoderma polysaccharides only activate the
macrophages, suggesting their diverse roles in activ ating
the innate and adaptive immunity (Yeh et al. 2010).
Li et al. (2010a) isolated Fungal Immunomodulatory
Proteins (FIP-gsi) comprised of 111 amino acids from
Ganoderma sinensis. Furthermore, FIP-gsi could enhance
the production levels of cytokinine, including interleukin-2,
3 and 4 interferon gamma, TNF-α, a nd interleukin receptor-
2 in mouse spleen cells. A novel immunomodulatory protein
(TVC) from the medicinal mushroom Trametes versicolor
markedly increa ses the proliferation of human peripheral
blood lymphoc ytes and enhances the pr oduction of both
nitric oxide and TNF-α by lipopolysaccharide-induced
murine macrophages. The results indicate that TVC is an
immunostimulant that can boost immune response (Feng et
al. 2011;Lietal.2011).
In several studies, a low-molecular weight protein fraction
(MLP-fraction) from the fruiting body of the maitake mush-
room Grifola frondosa that has potent anti-tumor activity was
isolated (Kodama et al. 2010). It was found that the MLP-
fraction enhanced the production of cytokines; interleukin-12
and interferon-gamma by splenocytes in tumor-bearing mice
and clearly exhibited an inhibitory effect on tumor cell
growth.
With advanced studies, many other potential immuno-
modulatory proteins have been reported from various spe-
cies of mushrooms, including APP and PCP-3A, which
were isolated from Auricularia polytricha and Pleurotus
citrinopileatus, respectively (Sheu et al. 2004; Chen et al.
2010a). As more and more studies reveal new species of
mushrooms, especially in the tropics (Dai 2010; Ge et al.
2010; Van de Putte et al. 2011; Zhao et al. 2010a, 2011) and
further chemical analyses are carried out for bioactive com-
pounds, we should expect many more novel and medicinal
compounds to be discovered from mushrooms. Although there
are increasing numbers of reports available for the identifica-
tion of mushroom proteins, the mechanisms of actions (e.g.
immunomodulation, anti-proliferation) are still poorly under-
stood and further studies are warranted (Li et al. 2010c).
Low-molecular-weight bioactive metabolites
(Fig. 4
, Table 3)
Mushrooms
produce a variety of complex low-molecular-
weight compounds with diverse chemical compositions that
we refer to in this review as phenolic compounds, polyketides,
triterpenoids and steroids specific to each mushroom (Zaidman
et al. 2005; Erkel and Anke 2008;Ferreiraetal.2010). The
majority of these compounds are not involved in the central
metabolic processes of the fungi (the generation of ener gy and
the formation of the building blocks of proteins, nucleic acids,
and cell membranes) and are known as secondary metabolites
(Abraham 2001; Petrova et al. 2008).
These substances are derived as intermediates in primary
metabolism, but they can be classified according to five
main metabolic sources. These are (1) amino acid-derived
pathways, (2) the shikimic acid pathway, (3) the acetate–
malonate pathway (4), the mevalonic acid pathway and (5)
the polysaccharides and peptidopolysaccharides derived
pathways. The acetate-malonate pathway and the mevalonic
acid pathways are most often involved in secondary metab-
olism of basidiomycetes and they produce a greater variety
of compounds (terpenoids, sesquiterpenoids, polyacety-
lenes) than the other pathways (Isaac 1997; Zaidman et al.
2005; Erkel and Anke 2008).
Many low molecular weight bioactive compounds isolated
from medicinal mushrooms show direct beneficial effects on
cancer development by modulating several cellular signal
transduction pathways (nuclear factor-κB pathway [NF-κB],
mitogen activated protein kinase pathway [MAPK]) and exert-
ing inhibitory effects on processes such as cell differentiation,
angiogenesis, carcinogenesis, and metastasis (Petrova et al.
2008; Zhong and Xiao 2009). A wide range of anti-tumor or
immunostimulating bioactive metabolites with low molecular
weights from mushrooms have been investigated (Table 3);
several promising compounds have been chosen and their
mechanism of action detailed below.
Cordycepin
Members of the genus Cordyceps are ascomycetou s fungi
commonly called caterpillar fungi and that grow as a result
16 Fungal Diversity (2012) 55:1–35
of a parasitic relationship between the fungus and the insect
larva (Chen and Jin 1992). The fungus germinates in living
organisms (in some cases the larvae), kills the insect, and
then the Cordyceps fruiting body grows from the body
of the insect (Chen and Jin 1992;Zhuetal.1998a, b).
Many species of Cordyceps have been identified for
medicinal purposes and use in health supplements. These
include C. sinensis, C. militaris, C. pruinosa, C. sub-
sessilis and C. ophioglossoides (Hobbs 1995; Holliday
and Cleaver 2008).
Cordycepin, or 3′-deoxyadenosine, is a derivative of
the nucleoside adenosine, whi ch was init ially extracted
from specimens in this genus but is now produced
synthetically (Paterson 2008). Cordycepin was first iso-
lated from a water extract of C. sinensis,andamajor
component of the butanol fraction of C. milit aris was
also identified as cordycepin by high performance liquid
chromatography (Jeong et al. 2011).
Cordycepin has two major effects on cells (Wong et al.
2010b). At a low dose cordycepin inhibits the uncontrolled
growth and division of the cells and at high doses it stops
cells from sticking together, which also inhibits growth.
Both of these effects probably have the same underlying
mechanism, which is that cordycepin interferes with protein
metabolism. At low doses, cordycepin interferes with the
production of mRNA and assembly of proteins. At higher
doses cordycepin has a direct impact on the production of
proteins. Wong et al. (2010b ) demonstrated that at low doses
cordycepin affects the poly (A) tails of specific mRNAs, and
this correlates with a reduction in cell proliferation. At
OH
OH
OH
O
Hispolon
N
N
N
N
O
NH
2
HOH
2
C
OH
Cordycepin
CH
3
CH
3
O
O
OH
CH
3
CH
3
CH
3
CH
3
H
H
Ergosterol peroxide
CH
3
CH
2
OH
CH
3
O
OH
CH
3
Irofulven
OH
OH
CH
3
CH
3
CH
3
CH
3
CH
3
O
O
O
O
OH
OH
O
OH
OH
O
OH
OH
Grifolin Phelli
g
ridin G
Fig. 4 Chemical structures
of selected low-molecular-
weight metabolites
Fungal Diversity (2012) 55:1–35 17
higher doses cordycepin also inhibits cell adhesion and
virtually abolishes protein synthesis, probably through its
effects on Akt and 4EBP phosphorylation. The most upstream
target of cordycepin at higher doses appears to be AMP-
activated kinase pathway, which it activates, leading to the
observed reduction in the mammalian target of rapamycin
signaling. Therefore, the two main effects of cordycepin
appear to be the inhibition of polyadenylation at low
doses and the activation of AMP-activated kinase pathway at
higher doses (Wong et al. 2010b).
An experimentally developed strain of Cordyceps sinensis
(Cs-4) has been used extensively in China, and products have
been developed with approval of the Chinese Health Ministry
(Zhu et al. 1998b).Severalanamorphicmycelialstrains,(e.g.,
Paecilomyces hepiali and Hirsutella hepiali) isolated from
natural C. sinensis have been manufactured in large quantity
by fermentation technology (Zhu et al. 1998a). This product
has been clinically used against many diseases, including
immune-stimulation and cancer prevention.
Cordycepin affects leukemia cells in humans by sig-
nificantly inducing apoptosis through a mitochondria-
mediated caspase-dependent pathway. Cordycepin is
thought to induce apoptosis of human leukemia cells
through a signaling cascade i nvolving a reactive oxygen
species-mediated caspase pathway (Khan et al. 2010;
Jeong et al. 2011)
Cordycepin has also been used as adjuvant treatment
in cancer prevention along with chemotherapy and ra-
diotherapy and has shown many beneficial effects on
patients, in some cases showing direct anti-tumor effects
(Zhu et al. 1998a, b). Ten pure compounds isolated
from the extracts of Cordyceps militaris, obtained
through a solid-state cultivation process, showed potent
anti-proliferation in PC-3 and colon 205 cells, while
only one compound displayed such an effect in HepG2
cells. This study provides support for the use of Cordyceps
militaris as an anti-inflammatory and anti-cancer agent (Lee
and Hong 2011).
R
3
R
4
R
5
R
2
R
1
H
3
C CH
3
CH
3
CH
3
H
CH
3
C
OOH
CH
3
R
6
H
3
C
Ganoderic acids
A : R
1
=R
3
=R
6
=O, R
2
=R
5
=β-OH, R
4
=H
B : R
1
=R
3
=R
5
=R
6
=O, R
2
=β-OH, R
4
=H
C : R
1
=R
3
=R
5
=R
6
=O, R
2
=β-OH, R
4
=H
D : R
1
=R
3
=R
5
=R
6
=O, R
2
= R
4
=β-OH
F : R
1
=R
2
=R
3
=R
5
=R
6
=O, R
4
=β-OH
G : R
1
=R
2
=R
4
=β-OH, R
3
=R
5
= R
6
=O
H : R
1
=β-OH, R
2
=R
3
= R
5
=R
6
=O, R
4
= β-OAc
Z : R
1
=β
β
-OH, R
2
=R
3
= R
4
=R
5
=R
6
=H
R
1
H
3
C CH
3
CH
3
CH
3
H
CH
3
CH
3
H
3
C
OH
R
2
HO
O
H
3
C CH
3
CH
3
CH
3
H
CH
3
CH
2
OH
CH
2
OH
H
3
C
Ganodermanontriol : R
1
=O, R
2
=OH Ganoderiol F
Ganodermanondiol : R
1
=O, R
2
=H
Lucidumol B : R
1
= -OH, R
2
=H
Fig. 4 (continued)
18 Fungal Diversity (2012) 55:1–35
Ergosterol
The pro-vitamin D
2
, ergosterol (ergosta-5,7,22-trien-3β-ol),
is abundant in lichens and mushrooms such as Agaricus
subrufescens, Ganoderma lucidum, Lentinula edodes
(Takaku et al. 2001; Paterson 2006; Phillips et al. 2011)
and Cordyceps sinensis and shows various types of bioac-
tivity (Li et al. 2004; Wu et al. 2007). Ergosterol is mostly
absent in the plant and animal kingdoms.
Ergosterol in mushrooms can be converted to vitamin D
2
by ultraviolet (UV) irradiation. Ergosterol undergoes photol-
ysis when exposed to UV light at wavelengths of 280–
320 nm, yielding a variety of photo irradiation products. The
principal products are provitamin D
2
, tachysterol, and lumi-
sterol. Ergosterol peroxide (5α,8α-epidioxy-22E-ergosta-
6,22-dien-3β-ol) is a steroidal derivative of ergosterol and
shows various biological activities with strong immunomod-
ulatory and anti-tumor activities (Krzyczkowski et al. 2009).
Inefficient programmed cell death (apoptosis) increases
tumor development and resistance to cancer therapy. Thus,
agents that induce apoptotic death of these cancer cells
would be useful in controlling this malignancy. Evaluation
of pro-apoptotic activity of ergosterol peroxide and (22E)-
ergosta-7,22-dien-5α-hydroxy-3,6-dione on prostate cancer
cells by Russo et al. (2010) indicated that these compounds
can reduce the growth of prostate cancer cells, at least in
part, by triggering an apoptotic process.
Ergosterol was isolated from A. subrufescens as an anti-
angiogenic substance and indications are that the anti-tumor
activity of ergosterol may be due to direct inhibition of
angiogenesis induced by solid tumors (Takaku et al. 2001).
Grifolin
Grifolin is a natural biologically active metabolite isolated
from the fruiting bodies of the mushroom Albatrellus
confluens that has shown m any pharmacological effects.
Earlier research has shown that grifolin acts as an antibiotic
(Hirata and Nahanishi 1950) and shows significant cholesterol
lowering activity, anti-oxidative activity and antimicrobial
activity (Sugiyama et al. 1992;Dingetal.2001;Nukataet
al. 2002).
Grifolin was identified as a potential antitumor agent that
can inhibit tumor cell growth by inducing apoptosis in vitro
for cancer cell lines. It was also shown that apoptosis of cells
was induced by the activation of caspase-8,-9, and -3, re-
lease of cytochrome c from mitochondria, with a decrease of
the Bcl-2 level and an increase of the Bax level (Ye et al.
2005; Song et al. 2007). Studies of molecular targets and the
signaling mechanism underlying the anti-cancer effect
found that grifolin significantly caused cell-cycle arrest in
the G1-phase that is responsible for the inhibition of the
ERK1/2 or the ERK5 pathway (Ye et al. 2007). Recent
evidence suggests that upregulation of death-associated pro-
tein kinase 1 (DAPK1) via the p53–DAPK1 pathway is an
important mechanism of grifolin that contributes to its ability
to induce an apoptotic effect (Luo et al. 2011).
Polyphenolic compounds (styrylpyrone-class of phenols)
Medicinal mushrooms have been reported to pr oduce a
variety of polyphenolic pigments, known as styrylpyrone-
class of phenols, derived from polyketide pathways, which
show significant biologica l effects, including anti-cancer
properties (Lee and Yun 2011). Styrylpyrone pigments are
common constituents of Phellinus spp. and Inonotus spp.
(Hymenochaetaceae). Hispidin was first isolated as a natu-
rally occurring styrylpyrone from Inonotus hispidus, and a
number of other hispidin-class metabolites have since been
discovered (Gonindard et al. 1997). Recent studies have
demonstrated that fruiting bodies of Phellinus igniarius, P.
linteus,
and Inonot
us obliqqus contain unique styrylpyrone
derivatives with many biological activities. Phelligridins A-J
were isolated from the ethanolic extract of Phellinus igniarius
together with inoscavin A and hispolon and showed anti-
oxidative and cytotoxic effects (Wang et al. 2007;Luetal.
2009; Huang et al. 2010).
Earlier studies showed that hispidin is more cytotoxic
toward cancerous cells (pancreatic duct and keratinocyte)
than normal cells (Gonindard et al. 1997). Hispolon from
ethanol extracts of Phellinus linteus fruiting bodies induces
apoptosis in human gastric cancer cells through a reactive
oxygen species (ROS)-mediated mitochondrial pathway (Lu
et al. 2009). This process is accompanied by the collapse of
mitochondrial membrane potential, the release of cyto-
chrome C and the activation of caspase-3 (Chen et al.
2006, 2008a). Hispolon has the ability to down regulate
some proto-oncogenes (MDM2) important in tumorigenesis
and a potential anti-tumor agent in breast and bladder cancers
(Lu et al. 2009). Recently, hispolon has been identified as an
anti-metastatic agent. It can inhibit the metastasis of SK-Hep1
cells by reduced expression of MMP-2, MMP-9, and uPA
through the suppression of various signaling pathways and
of the activity of PI3K/Akt and Ras homologue gene family
(Huang et al. 2010).
Phelligridins are a hispidin-class of derivatives (pyrano
[4,3-c][2]benzopyran-1,6-dione) from Inonotus and Phellinus
spp. Phelligridins (C-F) from P. igniarius showed in vitro
selective cytotoxicity against a human lung cancer cell line
and a liver cancer cell line (Mo et al. 2004;Wangetal.2007).
Highly oxygenated metabolites, including Phelligridins D, E
and G isolated from Inonotus and Phellinus spp. exhibited
significant free radical scavenging activity (Lee et al. 2007b;
Lee and Yun 2007). Phelligridin G was shown to be a powerful
Fungal Diversity (2012) 55:1–35 19
anti-oxidant with activity against human ovarian and colon
cancer cell lines (Wang et al. 2005). Co-culture of Inonotus
obliquus with Phellinus punctatusa led to the development of
a cost-effective strategy for up regulating biosynthesis
of bioactive metabolites with potent anti-tumor and anti-
proliferative effects on HeLa 22 9 cells. C hanges i n
metabolic profiles with metabolites, including phelligridin C,
phelligridin H, methyl inoscavin A, inoscavin C, methyl
davallialactone, provide positive prospects in the future
(Zheng et al. 2011).
Irofulven
Irofulven (6-hydroxymethylacylfulvene; MGI-114; MGI
PHARMA, Inc., Bloomington, MN) is a novel semi-
synthetic anti-cancer agent derived from the mushroom
toxin illudin-S (McMorris et al. 1996). The latter sesquiter-
penoid toxin produced by Omphalotus illudens was first
identified as a very potent antibiotic (Lehmann et al .
2003). The highly toxic properties of illudin-S promoted
the production of an analog with improved therapeutic po-
tential, a semi-synthetic derivative known as irofulven
(McMorris et al. 1996; McMorris 1999).
As an alkylating agent, irofulven has the ability to
covalently bind to biological macromolecules, to inhibit
DNA synthesis, and to induce apoptosis (Woynarowski
et al. 1997;Kelneretal.2008). In addition, it appears
to interfere with redox homeostasis, leading to protein
oxidation and mitochondrial dysfunction, which triggers
a proapoptotic signal. Its c ytotoxicity seems to be more
specifically directed against malignant cells and the
redox homeostasis that is maintained protects normal
cells from the effects of irofulven (Liang et al. 2001;
Leggas et al. 2002). In addition, an enhanced anti-tumor
activity of irofulven was observed in combination with
other anti-cancer agents (Poindessous et al. 2003; Kelner
et al. 2008).
Currently, irofulven is one of the most extensively stud-
ied anti-tumor drugs to have undergone many clin ical trials
but it still requires further clarification. Irofulven produced
different resu lts in phase I and phase II trials of human
cancer cell lines, including advanced melanoma (Pierson et
al. 2002), advanced renal cell carcinoma (Alexandre et al.
2007) and pretreated ovarian carcinoma (Seiden et al. 2006).
Studies showed that the cytotoxic activity of irofulven is
greater when it is combined with other anti-angiogenic or
chemotherapeutic drugs (Alexandre et al. 2004; Woo et al.
2005; Hilgers et al. 2006; Dings et al. 2008). Although
irofulven has undergone many clinical trials, its chemother-
apeutic behavior is not fully investigated, and irofulven has
some limitations in usage in different cancer cell lines, a
situation that requires further investigation.
Triterpenes of Ganoderma sp.
Ganoderma lucidum-derived polysaccharides prevent tumor
metastasis indirectly via the activation of an immune
response from the host organism, whereas triterpenes
suppress invasive behavior of the cancer cells directly.
Nume
rous
triterpenoids, including more than one hun-
dred pharmacologically-active metabolites, have been
discovered, and these compounds have been proven to
display wide-ranging biological activity (Cheng et al.
2010). These triterpenoids can be divided in to two
groups depending on the ligand bound to 26th carbone
position (C-26). One group has a C-26 carboxyl group and
these are referred to as ganoderic acids, whereas the other
group has a C-26 hydroxyl group and are known as Gano-
derma alcohols (Liu et al. 2010). Triterpenoid components,
including ganoderic acids, lucidimol-A, -B, ganodermanon-
diol, ganoderiol F and ganodermanontriol, have been demon-
strated to exert cytotoxic effects on cancer cells (Chen and
Chen 2003; Sliva 2003; Chang et al. 2006;Tangetal.2006a;
Weng and Yen 2010;Chinetal.2011).
Triterpenes isolated from species of Ganoderma have
anti-cancer properties (Cheng et al. 2010). Several cytotoxic
triterpenoids have been reported as having inhibitory activ-
ities against human cervical cancer cells (Cheng et al. 2010;
Xu et al. 2010). Triterpene-enriched extracts from Gano -
derma lucidum inhibit the growth of hepatoma cells via
suppressing protein kinase C, activating mitogen-activated
protein kin ases (Lin et a l. 2003). Ganoderic acid T also
induces apoptosis of metastatic lung tumor cells through
an intrinsic pathway related to mitochondrial dysfunction
(Tang et al. 2006b). Cytotoxicity of a ganoderic acid fraction
called GA-Me has been t ested on cultured h uman colon
cancer cells (Chen et al. 2008b). The activation of the
intrinsic mitochondria-dependent apoptotic pathway was
identified and the data suggest that GA-Me may be a natural
potential apoptosis inducing agent for human colon tumors
(Zhou et al. 2011)
Novel drug discovery from medicinal mushrooms
and clinical studies on patients
There has been growing interest in developing fungi and
mushroom-derived products as drugs or dietary supplements
and scientifically investigating the function of these products
(Lindequist et al. 2005; Aly et al. 2010;Jakopovich2011;Xu
et al. 2011). Medicinal mushrooms with biologically active
substances have been used in several human clinical trials and
have shown promising results as supportive treatment when
used along with conventional therapies (Zhuang and Wasser
2004; Wasser 2011). A trend toward integration of immune
potentiating agents with cancer surgery, chemotherapy, and
20 Fungal Diversity (2012) 55:1–35
radia tion therapy is now considerably advanced in many
Asian countries where mushroom preparations have been
traditional anti-cancer medicines for centuries (Jiang and Silva
2010;Jakopovich2011).
Many commercially developed mushroom polysaccharides
such as Lentinan from Lentinula edodes (Chihara et al. 1969,
1970;Hobbs2000), Schizophyllan (Sonifilan, Sizofiran, or
SPG), from Schizophyllum commune (Hobbs 2005), polysac-
charopeptide and polysaccharopeptide krestin, peptidoglucans
from Trametes versicolor (Hobbs 2004), maitake D-fraction
from Grifola frondosa (Zhuang and Wasser 2004; Boh and
Berivic 2007)andaGanoderma polysaccharide fraction from
G. lucidum (Yuen and Gohel 2005;Zhouetal.2005;Lin
2009; Mahajna et al. 2009; Wasser 2010)appeartomediate
anti-tumor activity by activating the immune system and have
proceeded through Phase I, II and III clinical trials, mainly in
Japan and China, while such trials are also occurring in the
United States and some European countries (Inoue et al. 1993;
Nanba 1997b;Mizuno1999b;Kidd2000; Yamashita et al.
2007;Jakopovich2011; Zhang et al. 2011).
Many experimental and clinical trials have been carried
out that show promising cancer inhibitory and immunosti-
mulatory activity in many other species of mushrooms,
including Cordyceps sinensis (Holliday and Cleaver 2008),
Flammulina velutipes (Maruyama and Ikekawa 2007), Ino-
notus obliquus (Mizuno et al. 1999;Parketal.2005) and
Phellinus linteus (Kim et al. 2007). Among low-molecular-
weight mushroom compounds, only a few of the numerous
newly discovered compounds have progressed to clinical
evaluation. Irofulven is the most extensively studied com-
pound in this group but needs future clinical confirmation
before being recommended for use as an anti-cancer drug
(Seiden et al. 2006; Alexandre et al. 2007).
What is the estimated use of medicinal mushrooms?
Cancer is one of the major chronic diseases responsible for
human deaths worldwide (Anon 2010
). Finding cures for
this disease
has been a challenge of great interest for
scientists throughout this and the previous century. Even
though it has proved difficult to find effective remedies
for this complex disease, supportive treatment to improve the
quality of life of cancer patients may significantly reduce
suffering.
Development of anti-cancer drugs has become a funda-
mental trend among the large pharmaceutical companies; they
spend billions of dollars on cancer research (Pollack 2009;
Smith and R yan 2009). Currently, the number of anti-cancer
drugs being tested on humans is more than twice the number
of experimental drugs for heart disease and stroke combined,
as well as being nearly twice the total for AIDS and all other
infectious diseases combined (Pollack 2009).
Exploration of natur al sources for novel bioactive anti-
tumor agents may provide leads or solutions for drug dis-
covery and development (Lindequist et al. 2010; Liu et al.
2010; Xu et al. 2010; Aly et al. 2011). Many promising
novel drugs have served as remarkable finds in the history
of disease treatments (Aly et al. 2011). Some of the key drug
products include antibiotics (penicillin, cephalosporins and
fusidic acid), anti-fungal agents (griseofulvin, strobilurins
and echinocandins) and a nti-cholesterol agents (statins,
Mevastatin and Lovastatin), and immunosuppressive drugs
(cyclosporine). In addition, some pharmaceutical drug prod-
ucts such as the ergot alkaloids were developed from fungal
bioactive compounds or their derivatives (Liu 2002; Li and
Vederas 2009; Liu et al. 2009b; Smith and Ryan 2009; Aly
et al. 2011). According to a 60-year review by Newman and
Cragg (2007) of the study on natural sources of drug products,
47% of anti-cancer drugs were actually developed as a result
of leads from natural products or directly derived from them.
A 50-year retrospective analysis of drug discovery from fungi
provides a comprehensive account of fungal secondary metab-
olites and their role as drug leads of enormous therapeutic
potential(Alyetal.2011).
Today, bioactive metabolites from medicinal mushrooms
produce beneficial effects not only as pharmaceutical drugs
but also as a novel class of supportive products with overall
immune enhancement (Jiang and Silva 2010; Jakopovich
2011). These include dietary supplements, functional foods
(nutraceuticals), nutri ceuticals (a new class of compounds
that have been extracted from either mushrooms or vegeta-
tive mycel ia). A refined or partially refined extract that is
consumed in the form of capsules or tablets as a dietary
supplement, but not as a food, can have potential thera peutic
applications as a mycopharm aceutical or as a designer food
that produces beneficial effects with regular usa ge in a
healthy diet (Chang and Buswell 2003; Chang 2006; Wasser
and Akavia 2008; Wasser 2010). Examples of the available
drug prod uc ts a nd supplement ary foods deve lo ped from
medicinal mushrooms that claim to provide benefic ial
effects on immune stimulation and help in cancer prevention
are shown in Table 4 and Plate 1.
Many researchers have come to the conclusion that, to
maximize a host-mediated response or to ‘awak en’ the im-
mune system, a mixture of polysaccharides with some com-
bination of mushroom extracts is best (Kurashige et al.
1997; Shamtsyan et al. 2004; Jakopovich 2011
). These
co
mbi
national effects appear to increase the number and
activity of killer T and natural killer lymphocytes. Combin-
ing species of medicinal mushrooms sends the immune
system multiple stimuli collectively, increasing intracellular
reactions, awakening the body’s natural defenses (Ivanković
et al. 2004; Zaidman et a l. 2005; Borchers et al. 2008;
Wasser 2010). One case study utilizing six medicinal mush-
rooms in breast cancer treatments resulted in complete
Fungal Diversity (2012) 55:1–35 21
Table 4 Examples of marketed products of mushroom extracts with claimed immunostimulatory activity
Product name Product function claim Fungus/extract present Web page
Dr Myko San – Health from Mushrooms Reducing the risk of the occurrence of malignant
diseases. Anti-tumor activity, without any
toxic side effects.
Different mushroom species www.mykosan.com
Jakopovich 2011
Ganoderma Lucidum Spore Anti-tumor and immuno-potentiating
properties (enhancing the functioning
of the immune system)
Ganoderma lucidum spore extract www.herbhorizon.net
Ganoderma_Spore.asp
Grifron Maitake Mushrooms Overall health and immune support Grifola frondosa www.shokos.com
MushroomWisdom.htm
I’m-Yunity
®
Maintaining white blood cell levels and
increasing immune proteins
COV-1
®
strain of Coriolus versicolor www.imyunity.com
MC-S (Metabolic Cell Support) Significantly enhances white blood cell
(immune cell) proliferation while simultaneously
suppressing cancer cell growth.
Ganoderma Lucidum, Lentinus edodes
(mycelia) Coriolus versicolor
www.mc-s.com.au
MycoPhyto® Complex Potential therapeutic value in the treatment of
human breast cancer
Blend of mushroom mycelia from Agaricus
subrufescens, Cordyceps sinensis, Coriolus
versicolor, Ganoderma lucidum, Grifola
frondosa and Polyporus umbellatus
Jiang and Silva 2010
www.econugenics.com
Red reishi Overall immunity and suppression of tumors Ganoderma lucidum fruit body and spores www.reishiscience.com
Super Royal Agaricus Mushroom Immune and kidney support Agaricus subrufescens-fruting body extract www.shokos.com/MushroomWisdom.htm
Grifola frondosa-Maitake TD fraction
The co-authors of the present paper have not confirmed these claims
22 Fungal Diversity (2012) 55:1–35
recovery (Shamtsyan et al. 2004). The formula inhibited the
growth of highly metastatic human breast cancer cells and
also suppressed metastatic potential of these cells wi thout
the side effects that are associated with cancer chemotherapy
(Shamtsyan et al. 2004; Jiang and Silva 2010).
Among the large pool of chemical metabolites found in
nature, discovery of biologically ac tive metabolites from
medicinal mushrooms give new insight to novel drug discov-
ery that might be used against cancer. The high structural
variability found in polysaccharide fractions and the unique
reactive properties of low molecular weight secondary metab-
olites show potential ability for use in anti-cancer remedies.
The high structural variability found in polysaccharides allows
them to have a high capacity for carrying biological informa-
tion(ChenandSeviour2007). Immunostimulatory activity as
a result of polysaccharides is believed to be mainly due to their
high molecular weight and the high structural complexity
associated with a branched triple helix structure (Bohn and
BeMiller 1995). However, these characteristics make it diffi-
cult to synthesize polysaccharides in large scale production and
certain physical properties restrict their pharmaceutical appli-
cability (Wasser 2002; Ohno 2005; Zhang et al. 2007; Chen
and Seviour 2007; Lehtovaara and Gu 2011).
Although the use of mushrooms in anti-cancer therapies
has promise, there are few conclusive mechanistic studies of
their constituents such as polysaccharides and evidence for
1
4
6
22
5
7
3
8
Plate 1 Examples of products marketed with claimed immune stimula-
tory and anti-cancer properties containing mushrooms or their extracts*.
1. Dr Myko San—Health from Mushrooms 2. Ganoderma Lucidum Spore
3.Grifron Maitake Mushrooms 4. I’m-Yunity
®
5. MC-S (Metabolic Cell
Support) 6. MycoPhyto® Complex 7. Red reishi 8. Super Royal Agaricus
Mushroom. * We have not confirmed the immune stimulatory and anti-
cancer effects of these products
Fungal Diversity (2012) 55:1–35 23
immunostimulatory action is still very hypothetical, espe-
cially where in vivo action is concerned. Another problem is
that the macromolecular glucans and other therapeutic poly-
mers from fungi may not exhibit favorable pharmacological
and pharmacokinetic properties. In terms of analytics, it is
also difficult to measure drug metabolism, which is one of
the major prerequisites for approval of “ethical” pharmaceu-
tical drugs. For this reason many of the mushroom derived
anti-cancer preparations remain as Over-the-counter drugs
(OTC drugs) or neutraceuticals. The recent papers by Chen
and Seviour (2007 ), Chan et al. (2009) and Wasser (2011)
have addressed the challenges (approval, analytical prob-
lems etc.) that are associated with the use of β-glucans in
cancer treatments and should be considered as further refer-
ences on how such topics can be addressed in a more
scientific manner.
Furthermore, mycelial cultures of various mushroom spe-
cies have also been shown to produce bioactive metabolites,
usually different from those found in the fruiting bodies. Of
particular note are the in vitro activities of terpe noids from
cultures of basidiomycete s (Peng et al. 2005;Erkeland
Anke 2008). The best known example for this is Pleuro-
mutilin, which is derived from mycelial cultures of the
genus Clitopilus (Hartley et al. 2009). Therefore, metab-
olites from cultures may not provide similar therapeutic
benefits as those that have been claimed in traditional
medicine. On the other hand, cultural extracts may produce
other medicinal benefits. Since this is not the purpose of this
review, readers should refer to other reviews (e.g., Abraham
2001; Shu et al. 2004; Zhong and Tang 2004; Lin and Liu
2006; Erkel and Anke 2008;Ferreiraetal.2010; Wasser 2011)
for further information. However, it is important to realize that
bioactive metabolites produced in the fruiting bodies may not
be produced in mycelial cultures and vice versa.
At present, commercial mushroom products are developed
either from mushrooms collected from field cultivation or
submerged cultures of the same species. Adding precursors to
the culture medium may facilitate or induce bioactive metabo-
lite production from a mycelium (similar or different content of
yield from those of fruiting bodies) through biotechnology and
bioconversion methods.Culture conditions such as pH can
affect the production of bioactive metabolites such as polysac-
charides by Agaricus subrufescens in batch cultures (Shu
et al. 2004). Zhong and Tang (2004) outlined several
important metabolites produced by mushroom cultivation
and advances in submerged culture of Ganoderma lucidum.
On the other hand, according to Heleno et al. (2011),
fruiting bodies of edible species of Bo letus can be used
directly in the hum an diet as health foods, due to their
primary metabolites such as proteins, carbohydrates, fatty
acids, mainly linoleic acid, sugars, mainly mannitol and
trehalose, and vitamins (tocopherols and ascorbic acid), as
well as antioxidan t secondary metabolites such as phenolic
derivatives. In addition, the volatile organic compounds
(VOC) identified from hydrodistillates and solvent extracts
of the fruiting bodies of Ganoderma lucidum were investi-
gated for cytotoxicity and antimicrobial activity by Campos
Ziegenbein et al. (2006). Recently, Kinge and Mih (2011)
demonstrated the cytotoxicity of three lanostane-type triterpe-
noids, isolated from fruiting bodies of Ganoderma zonatum,
against five human tumour cell lines. It should also be noted
that secondary metabolite (VOC) content can vary depending
on
wh
ether mushrooms are fresh, dried or cooked (Rapior et
al. 1997). This has an impact on the synergistic and/or additive
effects of the consumption of fruiting bodies in the human diet
as health foods.
Admittedly, most research has focused on mushroom sec-
ondary metabolites that directly affect intracellular transduc-
tion pathways, triggering specific signaling reactions that may
lead to cancer inhibition. The metabolites such as caffeic acid
phenethyl ester, cordycepin, panepoxydone and cycloepoxy-
don show specific cytotoxicity against tumor cells (Han et al.
2004; Zaidman et al. 2005; Erkel et al. 2007; Petrova et al.
2008, 2009; Yassin et al. 2008; Kudugunti et al. 2010). The
discovery of the metabolic action of cordycepin indicated that
the biochemical could be useful for treating a wide range of
different cancers (Wong et al. 2010b).
The advancements in scientific research directed to-
wards medicinal mushrooms and the activity of their
biometabolites and their behavior at the cellular level
make it possible to focus on new approaches (Wong et
al. 2010b;Wasser2011;Lietal.2010b). Significantly,
the knowledge of molecular biology, proteomics, genomics
and pharmacology should be integrated to develop new
approaches to apply these compounds to curing disease.
Conclusions and future prospective for novel drug
discovery from medicinal mushrooms
Mushrooms have been treasured as remedies for disease and
as natural health foods for thousands of years, and they are
incredibly popular foods in numerous countries throughout
the world (Lindequist et al. 2005 ;Ferreiraetal.2010).
Cancers, on the other hand, are chronic human diseases
which affect millio ns around in th e world. Even th ough
there has been remarkable progress in cancer trea tment
methods, this disease complex still causes serious and often
fatal problems. The patient’s desire for adequate support,
reduction of the side effects of conventional medicines,
strengthening of their immune system and enhancing quality
of life are currently topics of concern among physicians.
There is increasing evidence that medicinal mushrooms may
provide an array of medicinally important compounds that
have yet to be evaluated by West ern medical scientists.
Treatments based on medicinal mushrooms (mycotherapy/
24 Fungal Diversity (2012) 55:1–35
biological immunotherapy) fulfill many of the requirements
of supplementa ry c ance r treatments and may serve as a
direct remedy against cancer development .
The m ajor bioac tive metabol ites found in medicinal
mushrooms can be broadly categorized as high molecular
weight metabolites and low molecular weight metabolites.
High molecular weight metabolites such as polysacch arides,
protein polysaccharides and fungal immunomodulatory pro-
teins provide anti-cancer activity mainly thorough the acti-
vation of the immune system. Mushrooms may produce
large numbers of low molecular weight compounds that
not only activate the immune system but also control the
cellular transduction pathways responsible for cancer devel-
opment. Medicinal mushrooms are gifts from nature that
contain biologically active met abolites which can be used
as support remedies for cancer treatments. Additional studies
of the activities and mechanisms of action of these metabolites
are needed so to develop them as potent anti-cancer drugs.
New methods and techniques integrated with biotechnology
and other relevant disciplines are also required. In vivo exper-
imentation with high-quality, long-term double-blinded, clini-
cal studies with large trial populations will be needed to
confirm the safety and effects of these mushroom-derived
compounds on cancer patients.
More than 30 species of medicinal mushrooms are cur-
rently identified as sources for biologically active metabo-
lites with potential anti-cancer properties. However, much of
the evidence is based on traditional folklore (e.g., Tradition-
al Chinese Medicine), results of in vitro assays, as well as
conclusive in vivo data and even clinical traits (Jikai 2002).
One must be aware, however, that in vitro assays will only
give a hint as to the potential therapeutic value but are
not normal ly considered as valid proof. They mark the very
first steps in preclinical screening but are often used as adver-
tising arguments for traditional medicines. Therefore, future
investigations directed towards the structural suitability,
mechanisms, and metabolism of these compounds is war-
ranted to rationally improve them as potential drugs.
There are also many problems in the correct identifica-
tion, taxonomy and nomenclature of medi cinal mushrooms.
For example, con fusion exists with respect to the names
Agaricus blazei and Agaricus subrufescens or many poly-
pores (Kerrigan 2005; Dai 2010). There are, however, still
countries and regions that have not been studied for their
diversity of mushrooms. This is particularly true in tropical
regions of the world (Hawksworth 2001; Hyde 2001; Aly et
al. 2010; Boonyanuphap and Hansawasdi 2010). There is a
need to explore tropical countries for the presence of mush-
rooms and to assay their bioactive metabolites that can be used
as possible remedies for cancer treatments. A recent study
determined that high levels of β-glucans are found in wild
mushrooms in Thailand (Boonyanuphap and Hansawasdi
2010), while Hyde et al. (2010) reviewed the use of mushroom
in cosmetics, including evidence for certain medical properties
such as anti-aging. These studies indicate the need for inves-
tigations of wild mushrooms throughout poorly studied
regions, since the species present have medicinal, biochemical
and cultivatable potential. Studies are warranted to explore this
un-tapped resource for the isolation and production of novel
anti-cancer compounds of medicinal importance.
Acknowledgments This study was supported by a grant of the
French-Thai cooperation PHC SIAM 2011 (project 25587RA). The
authors are grateful to Professor Alain Fruchier (ENSCM, Montpellier,
France) for his helpful comments and corrections relating to chemistry.
The Global Research Network for Fungal Research and King Saud
University are also thanked for support.
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